This document describes a study that identified 1445 putative transcription factor genes in the mouse genome and mapped the expression patterns of over 1000 of these genes and associated co-regulators in developing mouse brains. The study found that 349 genes showed restricted expression patterns that adequately described the anatomical organization of the brain. A searchable brain atlas database was created containing a comprehensive inventory of murine transcription factors and their expression patterns.
This paper resulted from joint research between Thai and Oz researchers at the Australian Synchrotron in 2008. It represents a on-going collaboration between Siam Photon, Suranaree University of Technology, Monash University and the Australian Synchrotron
The IOSR Journal of Pharmacy (IOSRPHR) is an open access online & offline peer reviewed international journal, which publishes innovative research papers, reviews, mini-reviews, short communications and notes dealing with Pharmaceutical Sciences( Pharmaceutical Technology, Pharmaceutics, Biopharmaceutics, Pharmacokinetics, Pharmaceutical/Medicinal Chemistry, Computational Chemistry and Molecular Drug Design, Pharmacognosy & Phytochemistry, Pharmacology, Pharmaceutical Analysis, Pharmacy Practice, Clinical and Hospital Pharmacy, Cell Biology, Genomics and Proteomics, Pharmacogenomics, Bioinformatics and Biotechnology of Pharmaceutical Interest........more details on Aim & Scope).
All manuscripts are subject to rapid peer review. Those of high quality (not previously published and not under consideration for publication in another journal) will be published without delay.
The document discusses the Human Genome Project (HGP), including its goals, key milestones, and findings. It also examines some of the ethical, legal, and social issues raised by the HGP. In 3 sentences:
The HGP was an international scientific research project begun in 1990 that aimed to map and sequence the entire human genome. It was completed in 2003, revealing that the human genome contains over 3 billion DNA base pairs and around 30,000 genes. However, the HGP also raised important ethical questions around issues like privacy, ownership, justice, and the potential for discrimination.
The document provides an overview of the Human Genome Project (HGP). It describes the HGP's goal of mapping and sequencing the entire human genome. The HGP was an international research effort that worked alongside a private company, Celera Genomics, to complete a rough draft of the human genome by 2000. The completion of the HGP marked a major scientific achievement and has transformed fields like medicine, biotechnology, and genetics by providing a comprehensive map of the human genetic code.
The Human Genome Project mapped our entire genome in 2003, identifying 30,000-35,000 genes in our body. This allows scientists to identify traits and predict disorders, such as predicting disorders in babies before birth through gene mapping. Gene therapy uses vectors to carry normal genes into human cells to correct disorders by producing the correct protein and trait, with the hope that this continues to find cures for new diseases and viruses.
1. Several studies examined genes that regulate cell proliferation and differentiation in the respiratory epithelium, including Sox2 and SPDEF.
2. GATA-6 was shown to activate transcription of surfactant proteins A and TTF-1.
3. Additional research investigated the roles of surfactant proteins A and D in regulating phospholipid homeostasis and enhancing clearance of pathogens like RSV and bacteria from the lungs.
This study examined the microanatomy of the prostate gland in the opossum (Monodelphis domestica), a metatherian mammal, and compared it to the rat prostate. Immunohistochemistry was used to detect probasin, a conserved prostate protein, in tissue samples. Probasin was present in the posterior prostate of the opossum but not the anterior prostate, indicating regional specialization. While the structure of the opossum and rat prostates differed, probasin expression demonstrates evolutionary conservation of prostate function between metatherians and eutherians.
The document summarizes the human genome project. It discusses that the goal of the project was to map all the genes in the human DNA and determine the sequence of the 3 billion nucleotide base pairs. It was a large international project started in 1990 involving many universities. Some key milestones were determining the genes and their sequences, improving data analysis tools, and addressing ethical issues. The project provided benefits like understanding disease and developing personalized medicine. However, it also raised social issues regarding privacy of genetic data and potential discrimination. The sequencing revealed there are around 30,000 genes but many functions are still unknown. Future challenges include determining non-coding DNA and gene functions.
This paper resulted from joint research between Thai and Oz researchers at the Australian Synchrotron in 2008. It represents a on-going collaboration between Siam Photon, Suranaree University of Technology, Monash University and the Australian Synchrotron
The IOSR Journal of Pharmacy (IOSRPHR) is an open access online & offline peer reviewed international journal, which publishes innovative research papers, reviews, mini-reviews, short communications and notes dealing with Pharmaceutical Sciences( Pharmaceutical Technology, Pharmaceutics, Biopharmaceutics, Pharmacokinetics, Pharmaceutical/Medicinal Chemistry, Computational Chemistry and Molecular Drug Design, Pharmacognosy & Phytochemistry, Pharmacology, Pharmaceutical Analysis, Pharmacy Practice, Clinical and Hospital Pharmacy, Cell Biology, Genomics and Proteomics, Pharmacogenomics, Bioinformatics and Biotechnology of Pharmaceutical Interest........more details on Aim & Scope).
All manuscripts are subject to rapid peer review. Those of high quality (not previously published and not under consideration for publication in another journal) will be published without delay.
The document discusses the Human Genome Project (HGP), including its goals, key milestones, and findings. It also examines some of the ethical, legal, and social issues raised by the HGP. In 3 sentences:
The HGP was an international scientific research project begun in 1990 that aimed to map and sequence the entire human genome. It was completed in 2003, revealing that the human genome contains over 3 billion DNA base pairs and around 30,000 genes. However, the HGP also raised important ethical questions around issues like privacy, ownership, justice, and the potential for discrimination.
The document provides an overview of the Human Genome Project (HGP). It describes the HGP's goal of mapping and sequencing the entire human genome. The HGP was an international research effort that worked alongside a private company, Celera Genomics, to complete a rough draft of the human genome by 2000. The completion of the HGP marked a major scientific achievement and has transformed fields like medicine, biotechnology, and genetics by providing a comprehensive map of the human genetic code.
The Human Genome Project mapped our entire genome in 2003, identifying 30,000-35,000 genes in our body. This allows scientists to identify traits and predict disorders, such as predicting disorders in babies before birth through gene mapping. Gene therapy uses vectors to carry normal genes into human cells to correct disorders by producing the correct protein and trait, with the hope that this continues to find cures for new diseases and viruses.
1. Several studies examined genes that regulate cell proliferation and differentiation in the respiratory epithelium, including Sox2 and SPDEF.
2. GATA-6 was shown to activate transcription of surfactant proteins A and TTF-1.
3. Additional research investigated the roles of surfactant proteins A and D in regulating phospholipid homeostasis and enhancing clearance of pathogens like RSV and bacteria from the lungs.
This study examined the microanatomy of the prostate gland in the opossum (Monodelphis domestica), a metatherian mammal, and compared it to the rat prostate. Immunohistochemistry was used to detect probasin, a conserved prostate protein, in tissue samples. Probasin was present in the posterior prostate of the opossum but not the anterior prostate, indicating regional specialization. While the structure of the opossum and rat prostates differed, probasin expression demonstrates evolutionary conservation of prostate function between metatherians and eutherians.
The document summarizes the human genome project. It discusses that the goal of the project was to map all the genes in the human DNA and determine the sequence of the 3 billion nucleotide base pairs. It was a large international project started in 1990 involving many universities. Some key milestones were determining the genes and their sequences, improving data analysis tools, and addressing ethical issues. The project provided benefits like understanding disease and developing personalized medicine. However, it also raised social issues regarding privacy of genetic data and potential discrimination. The sequencing revealed there are around 30,000 genes but many functions are still unknown. Future challenges include determining non-coding DNA and gene functions.
This document contains a bibliography listing references related to the development of the brain and neural structures in various vertebrate and invertebrate species, including mice, frogs, lampreys, and zebrafish. The references cover topics such as gene expression patterns, brain regionalization, organization of subdivisions in the diencephalon and hypothalamus, and the evolution of the basal ganglia and forebrain connectivity across tetrapods. Most references are journal articles, but one web page is also included.
Managing Health and Disease Using Omics and Big DataLaura Berry
Presented at the NGS Tech and Applications Congress: USA. To find out more, visit:
www.global-engage.com
Michael Snyder is a Professor, Chair of Genetics and Director of the Stanford Center for Genomics and Personalized Medicine at Stanford University. In this presentation Michael discusses using omics and big data to predict disease risk and catch early disease onset.
Complete assignment on human Genome Projectaafaq ali
The document provides information about the Human Genome Project including:
1) It began in the late 1980s as a collaboration between the U.S. Department of Energy and the National Institutes of Health with a goal to map and sequence the entire human genome.
2) By 2003, the project had completed mapping the approximately 3 billion DNA base pairs that make up human DNA and identified over 30,000 human genes.
3) The project's completion enabled major advances in fields like medicine, biotechnology, and personalized healthcare by providing a better understanding of human genetics.
My talk to the PhD students NRP at the Doctoral Training Programme Summer Conference 2015, The Assembly House, Norwich, Thursday 18th June.
Notes and acknowledgments at http://kamounlab.tumblr.com/post/121748816600/what-are-world-class-science-outputs
The human genome project was started in 1990 with the goal of sequencing and ...Rania Malik
The Human Genome Project was a 13-year effort that began in 1990 with the goal of sequencing the entire human genome and identifying all of the genes in order to better understand genetic diseases and develop new treatments. It involved mapping the genome by identifying genetic markers and then sequencing DNA using techniques like cloning and polymerase chain reaction to amplify DNA for analysis. The project was completed in 2003, earlier than expected due to advances in sequencing technology, providing a full sequence of the human genome.
The document summarizes a talk on microbial agrogenomics. It discusses how genomics has advanced the understanding of plant-microbe interactions in several ways:
1) Genomes allow cataloging of genes and features in organisms and comparing common features between organisms that associate with phenotypes.
2) Multiple pathogen and plant genomes have enabled studying epidemiology through tracing historical origins, emergence in new areas, and host jumps.
3) Genomics provides diagnostic tools for precise pathogen identification needed for quarantine and legislation.
The human genome contains around 3 billion base pairs and 20,000-25,000 genes. Genes code for proteins and can vary in length from 1,000 to over 1.5 million base pairs. While genes make up about 1-1.4% of the genome, the remaining non-coding regions also play important regulatory roles. Genetic variations, from single mutations to complex interactions between multiple genes and the environment, underlie many diseases. New sequencing technologies are helping researchers better understand these relationships and develop personalized prevention and treatment approaches.
The document discusses the principal aims and applications of the Human Genome Project. The three main aims are to improve human genetics research infrastructure, establish DNA sequence as the interface between human and model organism biology, and improve DNA analytical biochemistry. Key applications discussed are molecular medicine like disease diagnosis, and using microbial genomes to research waste control and environmental cleanup. It provides examples of how genome sequencing is advancing fields like medicine, biotechnology, and environmental applications.
The Human Genome Project was a 13-year collaborative international project that was completed in 2003. It had the goals of identifying all the approximately 20,000-25,000 genes of the human DNA, determining the sequences of the chemical base pairs that make up human DNA, and storing this information in databases. The project used both hierarchical shotgun sequencing and whole genome shotgun sequencing techniques, as well as the Sanger dideoxy chain termination method, to fully map the human genome. The project raised several ethical, legal and social issues regarding privacy and use of genetic information.
The document provides an overview of bioinformatics and examples of how it is used at different biological scales and levels of complexity, from genomics to proteomics to biological networks and systems biology. It discusses how bioinformatics integrates biological data from different sources and scales to offer new biological insights. Examples are given of how bioinformatics is applied to analyze genomic, metagenomic, and proteomic data as well as protein structures and interactions.
A Critical Role of Erythropoietin Receptor in Neurogenesis and Post-Stroke Re...johnohab
Erythropoietin (EPO) is the principal growth factor regulating the production of red blood cells. Recent studies demonstrated that
exogenous EPO acts as a neuroprotectant and regulates neurogenesis. Using a genetic approach, we evaluate the roles of endogenous EPO
and its classical receptor (EPOR) in mammalian neurogenesis. We demonstrate severe and identical embryonic neurogenesis defects in
animals null for either the Epo or EpoR gene, suggesting that the classical EPOR is essential for EPO action during embryonic neurogenesis.
Furthermore, by generating conditional EpoR knock-down animals, we demonstrate that brain-specific deletion of EpoR leads to
significantly reduced cell proliferation in the subventricular zone and impaired post-stroke neurogenesis. EpoR conditional knockdown
leads to a specific deficit in post-stroke neurogenesis through impaired migration of neuroblasts to the peri-infarct cortex. Our results
suggest that both EPO and EPOR are essential for early embryonic neural development and that the classical EPOR is important for adult
neurogenesis and for migration of regenerating neurons during post-injury recovery.
This document discusses the impact of the Human Genome Project on medical advancement in India. It provides background on the human genome and the goals and processes of the Human Genome Project. Completing the human genome sequence provides benefits like enabling the diagnosis and treatment of genetic diseases in India. However, challenges remain like determining gene functions and understanding complex genetic traits. Overall, the document argues that further utilizing genome sequencing can help India better understand and manage its burden of genetic diseases.
1. Researchers injected mice with a virus that causes neurons activated during exploration of a novel context to express channelrhodopsin-2 (ChR2). They labeled dentate gyrus neurons activated during exploration of context A with ChR2.
2. On a later day, they optically stimulated the neurons labeled in context A while delivering a foot shock in a different context B, to test if this could generate a false fear memory for context A.
3. When later tested, mice that received optical stimulation of dentate gyrus neurons showed increased freezing in context A, where no shock was delivered, demonstrating the creation of a false fear memory through artificial means.
Presentation made by Abeliovich and Rhinn on the 20th of April, 2017, at the live webinar hosted by Alzforum: http://www.alzforum.org/webinars/webinar-cortex-aging-too-fast-blame-tmem106b-and-progranulin
What's In a Genotype?: An Ontological Characterization for the Integration of...mhb120
This document discusses challenges in integrating genetic variation data and summarizes efforts by the Monarch Initiative to address these challenges. Specifically, it discusses (1) reconciling genetic variation data associated with different levels (e.g. allele, gene), (2) integrating non-genomic forms of variation, and (3) creating semantic links to related biological data. The Monarch Initiative is developing the GENO ontology and using it in their data integration pipeline to standardize genetic variation data and infer new genotype-phenotype associations.
The document discusses the Human Genome Project, which had goals of sequencing the entire human genome to further medical research. It began in 1990 and was led by James Watson, while a private effort by Craig Venter's Celera Genomics also contributed. The first draft of the genome was published in 2001, two years ahead of schedule. The document outlines the hierarchical shotgun and whole genome shotgun strategies used to sequence the genome. Applications of sequencing include identifying disease-causing genes, discovering new genes, determining drug response, and DNA fingerprinting for forensics.
Los días 11 y 12 de diciembre de 2014, la Fundación Ramón Areces celebró el Simposio Internacional 'Neuropatías periféricas hereditarias. Desde la biología a la terapéutica' en colaboración con CIBERER-ISCIII y el Centro de Investigación Príncipe Felipe. El tipo más común de estas patologías es la enfermedad de Charcot-Marie-Tooth, un trastorno neuromuscular hereditario con una prevalencia estimada de 17-40 afectados por 100.000 habitantes. Durante estos dos días, investigadores mostraron sus avances en la mejora del diagnóstico y el tratamiento y, por ende, de la aproximación clínica y la calidad de vida de las personas afectadas por estas patologías.
The human genome project mapped the entire human genetic code and identified approximately 30,000 human genes, providing insights into the genetic basis of diseases and opportunities for new diagnostic tests and treatments. Gene therapy aims to treat diseases by modifying genes, either in vivo by introducing normal genes into patients' cells to replace mutated genes or ex vivo by extracting cells, modifying them genetically, and returning them to patients. While promising, gene therapy faces challenges in safety, delivery methods, and treating complex multi-gene disorders.
This document summarizes research on correlating MRI findings with neuropathological features in multiple sclerosis (MS). Key points include:
- MRI techniques like MTR can detect myelin and axonal loss validated by histology. Non-lesional white matter shows more extensive pathology than just lesions.
- Cortical grey matter also shows demyelination, neuronal loss, and atrophy correlated with disability.
- Spinal cord pathology including diffuse axonal loss and myelin damage contributes to disability, not just atrophy.
- Validating MRI with post-mortem tissue is important for diagnosis, predicting disease progression, and understanding substrates of disability in MS.
The study cloned and analyzed the GJB6 gene, which encodes the connexin 30 protein, from 16 bat species and 4 other mammals. Analysis showed purifying selection on GJB6 in mammals generally, maintaining its important role in hearing. One amino acid substitution was unique to bats, and 10 were shared among artiodactyls. The cytoplasmic loop and carboxy terminus were more variable than other domains in all mammals. The results demonstrate evolutionary conservation of GJB6 in mammals but also lineage-specific rapid evolution in some domains.
Bioinformatics is an interdisciplinary field that uses computational tools and techniques to analyze and interpret biological data. It plays a key role in areas like agriculture and healthcare. Some major areas of bioinformatics research include gene finding, protein structure prediction, and drug design. All organisms possess genetic material DNA that controls cell functioning and is the basis for inheritance. Understanding genomes, genes, and how genetic information is expressed presents many challenges. Comparative genomics through genome projects of different organisms can provide insights into evolution and aid in drug development.
This document contains a bibliography listing references related to the development of the brain and neural structures in various vertebrate and invertebrate species, including mice, frogs, lampreys, and zebrafish. The references cover topics such as gene expression patterns, brain regionalization, organization of subdivisions in the diencephalon and hypothalamus, and the evolution of the basal ganglia and forebrain connectivity across tetrapods. Most references are journal articles, but one web page is also included.
Managing Health and Disease Using Omics and Big DataLaura Berry
Presented at the NGS Tech and Applications Congress: USA. To find out more, visit:
www.global-engage.com
Michael Snyder is a Professor, Chair of Genetics and Director of the Stanford Center for Genomics and Personalized Medicine at Stanford University. In this presentation Michael discusses using omics and big data to predict disease risk and catch early disease onset.
Complete assignment on human Genome Projectaafaq ali
The document provides information about the Human Genome Project including:
1) It began in the late 1980s as a collaboration between the U.S. Department of Energy and the National Institutes of Health with a goal to map and sequence the entire human genome.
2) By 2003, the project had completed mapping the approximately 3 billion DNA base pairs that make up human DNA and identified over 30,000 human genes.
3) The project's completion enabled major advances in fields like medicine, biotechnology, and personalized healthcare by providing a better understanding of human genetics.
My talk to the PhD students NRP at the Doctoral Training Programme Summer Conference 2015, The Assembly House, Norwich, Thursday 18th June.
Notes and acknowledgments at http://kamounlab.tumblr.com/post/121748816600/what-are-world-class-science-outputs
The human genome project was started in 1990 with the goal of sequencing and ...Rania Malik
The Human Genome Project was a 13-year effort that began in 1990 with the goal of sequencing the entire human genome and identifying all of the genes in order to better understand genetic diseases and develop new treatments. It involved mapping the genome by identifying genetic markers and then sequencing DNA using techniques like cloning and polymerase chain reaction to amplify DNA for analysis. The project was completed in 2003, earlier than expected due to advances in sequencing technology, providing a full sequence of the human genome.
The document summarizes a talk on microbial agrogenomics. It discusses how genomics has advanced the understanding of plant-microbe interactions in several ways:
1) Genomes allow cataloging of genes and features in organisms and comparing common features between organisms that associate with phenotypes.
2) Multiple pathogen and plant genomes have enabled studying epidemiology through tracing historical origins, emergence in new areas, and host jumps.
3) Genomics provides diagnostic tools for precise pathogen identification needed for quarantine and legislation.
The human genome contains around 3 billion base pairs and 20,000-25,000 genes. Genes code for proteins and can vary in length from 1,000 to over 1.5 million base pairs. While genes make up about 1-1.4% of the genome, the remaining non-coding regions also play important regulatory roles. Genetic variations, from single mutations to complex interactions between multiple genes and the environment, underlie many diseases. New sequencing technologies are helping researchers better understand these relationships and develop personalized prevention and treatment approaches.
The document discusses the principal aims and applications of the Human Genome Project. The three main aims are to improve human genetics research infrastructure, establish DNA sequence as the interface between human and model organism biology, and improve DNA analytical biochemistry. Key applications discussed are molecular medicine like disease diagnosis, and using microbial genomes to research waste control and environmental cleanup. It provides examples of how genome sequencing is advancing fields like medicine, biotechnology, and environmental applications.
The Human Genome Project was a 13-year collaborative international project that was completed in 2003. It had the goals of identifying all the approximately 20,000-25,000 genes of the human DNA, determining the sequences of the chemical base pairs that make up human DNA, and storing this information in databases. The project used both hierarchical shotgun sequencing and whole genome shotgun sequencing techniques, as well as the Sanger dideoxy chain termination method, to fully map the human genome. The project raised several ethical, legal and social issues regarding privacy and use of genetic information.
The document provides an overview of bioinformatics and examples of how it is used at different biological scales and levels of complexity, from genomics to proteomics to biological networks and systems biology. It discusses how bioinformatics integrates biological data from different sources and scales to offer new biological insights. Examples are given of how bioinformatics is applied to analyze genomic, metagenomic, and proteomic data as well as protein structures and interactions.
A Critical Role of Erythropoietin Receptor in Neurogenesis and Post-Stroke Re...johnohab
Erythropoietin (EPO) is the principal growth factor regulating the production of red blood cells. Recent studies demonstrated that
exogenous EPO acts as a neuroprotectant and regulates neurogenesis. Using a genetic approach, we evaluate the roles of endogenous EPO
and its classical receptor (EPOR) in mammalian neurogenesis. We demonstrate severe and identical embryonic neurogenesis defects in
animals null for either the Epo or EpoR gene, suggesting that the classical EPOR is essential for EPO action during embryonic neurogenesis.
Furthermore, by generating conditional EpoR knock-down animals, we demonstrate that brain-specific deletion of EpoR leads to
significantly reduced cell proliferation in the subventricular zone and impaired post-stroke neurogenesis. EpoR conditional knockdown
leads to a specific deficit in post-stroke neurogenesis through impaired migration of neuroblasts to the peri-infarct cortex. Our results
suggest that both EPO and EPOR are essential for early embryonic neural development and that the classical EPOR is important for adult
neurogenesis and for migration of regenerating neurons during post-injury recovery.
This document discusses the impact of the Human Genome Project on medical advancement in India. It provides background on the human genome and the goals and processes of the Human Genome Project. Completing the human genome sequence provides benefits like enabling the diagnosis and treatment of genetic diseases in India. However, challenges remain like determining gene functions and understanding complex genetic traits. Overall, the document argues that further utilizing genome sequencing can help India better understand and manage its burden of genetic diseases.
1. Researchers injected mice with a virus that causes neurons activated during exploration of a novel context to express channelrhodopsin-2 (ChR2). They labeled dentate gyrus neurons activated during exploration of context A with ChR2.
2. On a later day, they optically stimulated the neurons labeled in context A while delivering a foot shock in a different context B, to test if this could generate a false fear memory for context A.
3. When later tested, mice that received optical stimulation of dentate gyrus neurons showed increased freezing in context A, where no shock was delivered, demonstrating the creation of a false fear memory through artificial means.
Presentation made by Abeliovich and Rhinn on the 20th of April, 2017, at the live webinar hosted by Alzforum: http://www.alzforum.org/webinars/webinar-cortex-aging-too-fast-blame-tmem106b-and-progranulin
What's In a Genotype?: An Ontological Characterization for the Integration of...mhb120
This document discusses challenges in integrating genetic variation data and summarizes efforts by the Monarch Initiative to address these challenges. Specifically, it discusses (1) reconciling genetic variation data associated with different levels (e.g. allele, gene), (2) integrating non-genomic forms of variation, and (3) creating semantic links to related biological data. The Monarch Initiative is developing the GENO ontology and using it in their data integration pipeline to standardize genetic variation data and infer new genotype-phenotype associations.
The document discusses the Human Genome Project, which had goals of sequencing the entire human genome to further medical research. It began in 1990 and was led by James Watson, while a private effort by Craig Venter's Celera Genomics also contributed. The first draft of the genome was published in 2001, two years ahead of schedule. The document outlines the hierarchical shotgun and whole genome shotgun strategies used to sequence the genome. Applications of sequencing include identifying disease-causing genes, discovering new genes, determining drug response, and DNA fingerprinting for forensics.
Los días 11 y 12 de diciembre de 2014, la Fundación Ramón Areces celebró el Simposio Internacional 'Neuropatías periféricas hereditarias. Desde la biología a la terapéutica' en colaboración con CIBERER-ISCIII y el Centro de Investigación Príncipe Felipe. El tipo más común de estas patologías es la enfermedad de Charcot-Marie-Tooth, un trastorno neuromuscular hereditario con una prevalencia estimada de 17-40 afectados por 100.000 habitantes. Durante estos dos días, investigadores mostraron sus avances en la mejora del diagnóstico y el tratamiento y, por ende, de la aproximación clínica y la calidad de vida de las personas afectadas por estas patologías.
The human genome project mapped the entire human genetic code and identified approximately 30,000 human genes, providing insights into the genetic basis of diseases and opportunities for new diagnostic tests and treatments. Gene therapy aims to treat diseases by modifying genes, either in vivo by introducing normal genes into patients' cells to replace mutated genes or ex vivo by extracting cells, modifying them genetically, and returning them to patients. While promising, gene therapy faces challenges in safety, delivery methods, and treating complex multi-gene disorders.
This document summarizes research on correlating MRI findings with neuropathological features in multiple sclerosis (MS). Key points include:
- MRI techniques like MTR can detect myelin and axonal loss validated by histology. Non-lesional white matter shows more extensive pathology than just lesions.
- Cortical grey matter also shows demyelination, neuronal loss, and atrophy correlated with disability.
- Spinal cord pathology including diffuse axonal loss and myelin damage contributes to disability, not just atrophy.
- Validating MRI with post-mortem tissue is important for diagnosis, predicting disease progression, and understanding substrates of disability in MS.
The study cloned and analyzed the GJB6 gene, which encodes the connexin 30 protein, from 16 bat species and 4 other mammals. Analysis showed purifying selection on GJB6 in mammals generally, maintaining its important role in hearing. One amino acid substitution was unique to bats, and 10 were shared among artiodactyls. The cytoplasmic loop and carboxy terminus were more variable than other domains in all mammals. The results demonstrate evolutionary conservation of GJB6 in mammals but also lineage-specific rapid evolution in some domains.
Bioinformatics is an interdisciplinary field that uses computational tools and techniques to analyze and interpret biological data. It plays a key role in areas like agriculture and healthcare. Some major areas of bioinformatics research include gene finding, protein structure prediction, and drug design. All organisms possess genetic material DNA that controls cell functioning and is the basis for inheritance. Understanding genomes, genes, and how genetic information is expressed presents many challenges. Comparative genomics through genome projects of different organisms can provide insights into evolution and aid in drug development.
An Evolutionarily Conserved Long Noncoding RNA TUNA Controls Pluripotency and...Zach Rana
Here are 3 sentences summarizing the key points of the document:
1) An unbiased genome-scale RNAi screen in mouse embryonic stem cells identified 20 long noncoding RNAs (lincRNAs) required for maintenance of pluripotency, including linc86023 (also known as TUNA or megamind).
2) TUNA was found to form a complex with RNA-binding proteins at the promoters of pluripotency genes Nanog, Sox2, and Fgf4, and its depletion inhibited neural differentiation and impaired proliferation of mouse ESCs.
3) TUNA showed evolutionary conservation and central nervous system-restricted expression in vertebrates, and its knockdown
Se han hecho públicos los resultados de un prometedor trabajo encabezado por investigadores del Hospital Infantil de Boston y la Facultad de Medicina de Harvard, que ha conseguido recuperar, utilizando terapia génica, parte de la audición de ratones sordos. El artículo, que ha merecido la portada de la prestigiosa revista Science Translational Medicine, promete abrir un abanico terapéutico para el tratamiento de la sordera genética en los seres humanos.
This study characterized the response properties of auditory nerve fibers in mice by recording from over 250 fibers in the CBA/CaJ and C57BL/6 mouse strains. The study found that mouse auditory nerve fibers showed similar response properties to other mammals, including sharp tuning that increased with frequency from 2.5-70kHz. Spontaneous firing rates ranged from 0-120 spikes per second. Dynamic ranges for high spontaneous rate fibers were smaller than other mammals. Phase locking was seen below 4kHz with lower synchronization than cats but similar to guinea pigs. The only interstrain difference was higher thresholds in C57BL/6 at high frequencies.
The mammalian-specific Tex19.1 gene plays an essential role in spermatogenesi...Yara Tarabay
The mammalian-specific Tex19.1 gene plays an important role in spermatogenesis and placenta-supported development in mice. Deletion of the Tex19.1 gene in mice leads to impaired spermatogenesis and male sterility. It also causes perinatal lethality due to placental defects, resulting in severe hypotrophy in newborn homozygous mutant mice regardless of sex. Furthermore, deletion of Tex19.1 results in overexpression of retrotransposons, including MMERVK10C, in embryonic stem cells and testes. This suggests Tex19.1 plays a role in controlling retrotransposon expression and has dual functions in male fertility and placental development.
This document describes the identification of FLOWERING LOCUS T (FT) through an activation tagging screen in Arabidopsis thaliana. The 1733 mutant tagged line flowered early and had terminal flowers. Sequencing of the tagged gene revealed it to be FT. Overexpression of FT using the 35S promoter recapitulated the 1733 phenotype, flowering very early with few leaves. FT was found to act partially downstream of CONSTANS (CO) to promote flowering in response to day length. Unlike many floral regulators, the FT protein sequence does not suggest it directly controls transcription.
The document summarizes a study that examined the grey matter of multiple sclerosis patients. The study found an absence of functional peroxisomes in the grey matter of multiple sclerosis patients. Peroxisomes help break down toxins and fatty acids in neural cells. The study used staining, gene expression analysis, and fatty acid quantification to show that multiple sclerosis grey matter has significantly fewer peroxisomes and accumulates more fatty acids compared to normal grey matter. As multiple sclerosis progresses, the levels of a peroxisome membrane protein called PMP70 decrease, indicating fewer peroxisomes over time. This absence of peroxisomes may contribute to multiple sclerosis progression by hindering neural cell function.
This study examined the connections of primary auditory and visual areas in the prairie vole brain using tracer injections. The results showed that the primary auditory cortex had intrinsic connections and connections with other auditory areas, multimodal cortex, primary visual cortex, and primary somatosensory cortex. The primary visual cortex had intrinsic connections and connections with other visual areas, multimodal cortex, auditory cortex, and somatosensory cortex in some cases. Both auditory and visual areas received thalamic input from auditory and visual thalamic nuclei. The connections suggest multisensory integration occurs in primary sensory areas of the prairie vole, which may relate to their social behaviors that rely heavily on audition.
1. There are at least two populations of Tbr2+ cells in the embryonic mouse midbrain - a lateral population and a medial "bridge" population.
2. Immunohistochemistry results from E13.5 to P0 suggest that the Tbr2+ midbrain cells are no longer mitotic, following a conserved transcription factor program of Pax6 -> Tbr2 -> Tbr1 seen in other brain regions.
3. Using Ai14/EoCreERT2 lineage tracing mice, the fate of the early Tbr2+ midbrain population can be tracked to maturity, though longer experiments are needed to identify the adult midbrain nucleus derived from these cells.
Inhibition of the topoisomerase 2 enzyme with HU-331 in zebrafish results in axonal pathfinding defects in neural development. Behavioral assays at 48 hpf and 96 hpf showed significant differences in the startle response of treated zebrafish, indicating gross neurological defects. Immunohistochemistry experiments revealed aberrant crossing of Mauthner neurons in the hindbrain and defective pathfinding of motor axons in treated zebrafish. This suggests topoisomerase 2 is required for proper axonal pathfinding during neural development. Future work will examine how topoisomerase 2 knockdown affects neuronal survival and gene expression related to axon guidance.
This article reports the detection of two gas clouds with no discernible elements heavier than hydrogen, representing the lowest heavy-element abundance observed in the early universe. One cloud at z=3.4 exhibits a deuterium abundance matching predictions from Big Bang nucleosynthesis, providing direct evidence for the standard cosmological model. The sparse metal enrichment of these clouds implies an inhomogeneous process for transporting heavy elements from galaxies into the surrounding intergalactic medium.
This presentation contains basic information about the mouse being used as a model organism, its genome, how the genome of the mouse was sequenced and a comparison between mouse genome and human genome.
The document summarizes key aspects of the human genome and genome projects. It discusses that a genome contains an organism's complete DNA including all genes. It describes the physical structure of human DNA including nuclear DNA, mitochondrial DNA, and RNA. It provides details on the goals and completion of the Human Genome Project in 2003, two years ahead of schedule. The project aimed to identify all human genes and map the 3 billion base pairs of human DNA.
cloning. Second, it is sensitive. Activities canbe detected WilheminaRossi174
cloning. Second, it is sensitive. Activities can
be detected in the purified GST-ORF pools
that simply cannot be detected in extracts or
cells, the starting point of both conventional
purification and expression cloning. Because
the GST-ORFs are individually expressed at
high levels and are largely free of extract
proteins after purification, activities can be
measured for hours without competing activ-
ities that destroy the substrate, the product, or
the enzymes.
In addition to the conventional use demon-
strated here, this array could be used in two
other ways: (i) to determine the range of poten-
tial substrate proteins for any protein-modifying
enzyme (such as a protein kinase) before genet-
ic or biochemical tests to establish authentic
substrates and (ii) to identify genes encoding
proteins that bind any particular macromole-
cule, ligand, or drug. Thus, one could rapidly
ascribe function to many presently unclassified
yeast proteins, complementing other genomic
approaches to deduce gene function from ex-
pression patterns, mutant phenotypes, localiza-
tion of gene products, and identification of in-
teracting partners.
References and Notes
1. H. Simonsen and H. F. Lodish, Trends Pharmacol. Sci.
15, 437 (1994).
2. Plasmid pYEX 4T-1 (Clontech, Palo Alto, CA) was
modified by the addition of a 140-nucleotide recom-
bination domain, 39 of its Eco RI site, linearized within
the recombination domain by restriction digestion,
and cotransformed with a genomic set of reamplified
ORFs that had the same ends as the linearized plas-
mid [ J. R. Hudson Jr. et al., Genome Res. 7, 1169
(1997)] into strain EJ 758 [MATa his3-D200, leu2-
3,112, ura3-52, pep4::URA3], a derivative of JHRY-
20-2Ca (5). Transformants obtained on synthetic
minimal (SD) 2 Ura drop-out plates [F. Sherman,
Methods Enzymol. 194, 3 (1991)] (.100 in all cases,
and more than five times the cut vector in 97% of the
cases) were eluted in batch and saved in 96-well
microtiter plates. The library contains 6080 ORF-
containing strains and 64 strains with vector only.
3. Cell patches were inoculated in SD 2 Ura liquid
medium, grown overnight, reinoculated, and grown
overnight in SD 2 Ura 2 Leu medium, and then
inoculated into 250 ml of SD 2 Ura 2 Leu medium,
grown to absorbance at 600 nm of 0.8, and induced
with 0.5 mM copper sulfate for 2 hours before har-
vest [I. G. Macreadie, O. Horaitis, A. J. Verkuylen,
K. W. Savin, Gene 104, 107 (1991)]. Cells were re-
suspended in 1 ml of buffer [50 mM tris-HCl (pH 7.5),
1 mM EDTA, 4 mM MgCl2, 5 mM dithiothreitol (DT T),
10% glycerol, and 1 M NaCl] containing leupeptin (2
mg/ml) and pepstatin (1 mg/ml), and extracts were
made with glass beads [S. M. McCraith and E. M.
Phizicky, Mol. Cell. Biol. 10, 1049 (1990)], followed
by supplementation with 1 mM phenylmethylsulfo-
nyl fluoride and centrifugation. GST-ORF fusion pro-
teins were purified by glutathione agarose chroma-
tography in buffer containing 0.5 M NaCl, essentially
as described [ J. ...
This study analyzed DNA sequences from nine genes (three plastid, three mitochondrial, and three nuclear) from 100 plant species to better understand relationships among basal angiosperms. Phylogenetic analyses strongly supported Amborella, Nymphaeaceae, and Austrobaileyales as the earliest diverging lineages of flowering plants. The analyses also supported magnoliids as a monophyletic group consisting of Magnoliales, Laurales, Piperales, and Canellales. However, relationships among Ceratophyllum, Chloranthaceae, magnoliids, monocots, and eudicots were mostly unresolved with low support. Examination of substitution patterns supported placement of Amborella and others
A consortium of 440 scientists from 32 laboratories characterized functional elements in the human genome as part of the ENCyclopedia Of DNA Elements (ENCODE) project. They found that 80% of the genome is biochemically active, with millions of regulatory elements such as promoters, enhancers, and insulators. Many of these elements interact with genes over long distances to control gene expression. This study significantly changes understanding of how the genome works.
The document summarizes the Human Genome Project (HGP). It began in 1990 with the goal of identifying all the genes in human DNA and determining the sequence of the 3 billion chemical base pairs. The 13-year project was completed in 2003 and involved international collaboration. It mapped the human genome and identified approximately 20,000-25,000 human genes. The HGP provided insights into human evolution and has applications in medicine, such as for identifying genes associated with diseases. It also advanced bioinformatics for analyzing large DNA datasets.
20140824 Abnormalities in human pluripotent cells due to reprogramming mechan...Alim Polat
This study compares genetic and epigenetic abnormalities in three types of human pluripotent stem cells: induced pluripotent stem cells (iPS cells), nuclear transfer embryonic stem cells (NT ES cells), and in vitro fertilization embryonic stem cells (IVF ES cells). The researchers found that both iPS cells and NT ES cells derived from the same somatic cells contained similar numbers of copy number variations, whereas DNA methylation and gene expression profiles of NT ES cells more closely matched those of IVF ES cells. The results suggest that human somatic cells can be faithfully reprogrammed to pluripotency by somatic cell nuclear transfer and may be better suited than iPS cells for cell replacement therapies due to avoiding
20140824 Abnormalities in human pluripotent cells due to reprogramming mechan...
Gray et al. 2004 Science copy
1. 8. C. Toyoshima, H. Nomura, T. Tsuda, Nature 432, 361
(2004).
9. T. L.-M. Sørensen et al., J. Biol. Chem. 279, 46355
(2004).
10. J. V. Møller, G. Lenoir, M. Le Maire, B. S. Juul, P. Champeil,
Ann. N. Y. Acad. Sci. 986, 82 (2003).
11. J. D. Clausen, B. Vilsen, D. B. McIntosh, A. P. Einholm,
J. P. Andersen, Proc. Natl. Acad. Sci. U.S.A. 101,
2776 (2004).
12. Materials and methods are available as supporting
material on Science Online.
13. S. Danko, K. Yamasaki, T. Daiho, H. Suzuki, J. Biol.
Chem. 279, 14991 (2004).
14. C. Toyoshima, G. Inesi, Annu. Rev. Biochem. 73, 269
(2004).
15. A. Barth, W. Kreutz, W. Mantele, J. Biol. Chem. 272,
25507 (1997).
16. I. M. Glynn, J. Physiol. 462, 1 (1993).
17. T. Sørensen, B. Vilsen, J. P. Andersen, J. Biol. Chem.
272, 30244 (1997).
18. B. Forbush III, I. Klodos, in The Sodium Pump:
Structure, Mechanism, and Regulation, J. H. Kaplan,
P. de Weer, Eds. (Rockefeller Univ. Press, New York,
1991), pp. 211.
19. F. Cornelius, J. V. Møller, FEBS Lett. 284, 46 (1991).
20. X. Yu, S. Carroll, J. L. Rigaud, G. Inesi, Biophys. J. 64,
1232 (1993).
21. D. Levy, M. Seigneuret, A. Bluzat, J. L. Rigaud, J. Biol.
Chem. 265, 19524 (1990).
22. X. Yu, L. Hao, G. Inesi, J. Biol. Chem. 269, 16656 (1994).
23. T. Seekoe, S. Peall, D. B. McIntosh, J. Biol. Chem. 276,
46737 (2001).
24. M. Toustrup-Jensen, B. Vilsen, J. Biol. Chem. 278, 11402
(2003).
25. M. Shigekawa, L. J. Pearl, J. Biol. Chem. 251, 6947 (1976).
26. W. P. Jencks, J. Biol. Chem. 264, 18855 (1989).
27. W. L. DeLano, PyMOL Molecular Graphics System (2002);
available online at http://www.pymol.sourceforge.net.
28. C. R. Lancaster, Nature 432, 286 (2004).
29. We thank B. Holm, B. Nielsen, and C. Lauridsen for
expert technical assistance; the staff at the Protein
Structure Factory beamline BL14.1 of Free University
Berlin at Berliner Elektronenspeicherring-Gesellschaft
fu¨r Synchrotronstrahlung m. b. H., the staff at European
Synchrotron Radiation Facility (ESRF) beamline ID29;
J. L. Karlsen and R. Jørgensen for extensive computer
support; and J. Nyborg for fruitful scientific discussions.
This work was supported by an Ole Rømer Research
grant; the Center for Structural Biology; the Dansync
program under the Danish Natural Science Research
Council; a grant from the Lundbeck Foundation (P.N.),
and grants from the Danish Medical Research Council,
Aarhus University Research Foundation, and Novo
Nordic Foundation (J.V.M.). Coordinates and structure-
factor amplitudes have been deposited to the Protein
Data Bank under code 1XP5.
Supporting Online Material
www.sciencemag.org/cgi/content/full/306/5705/2251/
DC1
Materials and Methods
Figs. S1 to S4
Table S1
Movie S1
12 October 2004; accepted 23 November 2004
10.1126/science.1106289
Mouse Brain Organization Revealed
Through Direct Genome-Scale
TF Expression Analysis
Paul A. Gray,1,3
*. Hui Fu,2,3
* Ping Luo,1,3
* Qing Zhao,4
Jing Yu,5
Annette Ferrari,3
Toyoaki Tenzen,5
Dong-in Yuk,4
Eric F. Tsung,6
-
Zhaohui Cai,6
John A. Alberta,3
Le-ping Cheng,1,3
Yang Liu,1,3
Jan M. Stenman,5
M. Todd Valerius,5
Nathan Billings,4
Haesun A. Kim,2,3
` Michael E. Greenberg,1,8
Andrew P. McMahon,5
David H. Rowitch,4,7
Charles D. Stiles,2,3
¬ Qiufu Ma1,3
¬
In the developing brain, transcription factors (TFs) direct the formation of a
diverse array of neurons and glia. We identifed 1445 putative TFs in the
mouse genome. We used in situ hybridization to map the expression of over
1000 of these TFs and TF-coregulator genes in the brains of developing mice.
We found that 349 of these genes showed restricted expression patterns that
were adequate to describe the anatomical organization of the brain. We
provide a comprehensive inventory of murine TFs and their expression
patterns in a searchable brain atlas database.
The mammalian nervous system contains
thousands of distinct neuronal and glial cell
types that are distinguished on the basis of
morphology, projection, and marker gene ex-
pression (1). Transcription factors (TFs) play a
pivotal role in brain development by directing
the formation of neurons and glia from uncom-
mitted progenitor cells (2). To determine the
extent to which TFs describe the diversity of
the mammalian central nervous system (CNS),
we visualized the spatial and temporal expres-
sions of TF-encoding genes on a genome-wide
scale in the developing mouse CNS.
To identify unique genomic loci that encode
putative TFs in the mouse genome, we ana-
lyzed and annotated existing public and private
databases (3–6). Candidates were classified as
TFs only if their predicted protein sequence
included a Protein Families Database (Pfam)–
defined TF-DNA binding domain (3). We iden-
tified 1445 unique transcriptional units in the
mouse genome with putative TF-DNA bind-
ing domains. The nonoverlapping genes for
each DNA binding family (7, 8) are summa-
rized in Table 1 and tables S1 and S2. Recent
protein prediction databases have estimated that
there are over 2300 different TF proteins in the
mouse genome (6, 9). This higher number is
primarily due to the separate counting of each
possible protein variant as a unique transcrip-
tional unit, as well as the duplicate counting of
genes with multiple DNA binding domains.
The largest single class of TF proteins (È678
members, not including nuclear hormone re-
ceptors) was the zinc-finger family. Homeo-
box TFs had 227 members, and there were 50
nuclear hormone receptors and 116 basic helix-
loop-helix (bHLH) TFs (Table 1 and table S1).
The human genome encodes 20,000 to 25,000
genes (10). If a similar number of genes are
encoded in the mouse genome, then TF genes
make up more than 7% of the total.
We designed gene-specific polymerase
chain reaction (PCR) primer pairs to produce
in situ hybridization probes for 1174 TF-
encoding genes. This probe set covers 91% of
genes that belong to 32 out of the 33 major TF
families (table S1). For the remaining (also
the largest) gene family, which encodes zinc-
finger proteins (divided into 12 subgroups),
71% of the genes were covered by the probe
set (table S1). These primers were used to
perform PCR on cDNA templates prepared
from embryonic day 13.5 (E13.5) and newborn
Epostnatal day zero (P0)^ mouse brains. A small
number of additional probes were acquired
from embryonic mouse kidney or testis cDNA.
Among the 1174 TF-encoding genes screened,
972 (83%) showed positive PCR products. We
monitored the recovery of nuclear hormone
receptors as a metric for sensitivity. We cloned
46 of the 50 nuclear hormone receptors that are
encoded in the mouse genome. Only one nu-
clear hormone receptor known to be expressed
in the brain, the androgen receptor (11), was
missed by our procedure. In total, 983 TF-
encoding genes were subsequently cloned or
acquired (Table 1 and table S1). We also cloned
104 transcription cofactor genes (Table 1 and
table S1), yielding a total number of 1087
genes, which are collectively referred to as TF-
encoding genes. These cloned in situ plasmids
1
Department of Neurobiology, 2
Department of Mi-
crobiology and Molecular Genetics, Harvard Medical
School, Boston, MA 02115, USA. 3
Department of
Cancer Biology, 4
Department of Pediatric Oncology,
Dana-Farber Cancer Institute, 1 Jimmy Fund Way,
Boston, MA 02115, USA. 5
Department of Molecular
and Cellular Biology, Harvard University, 16 Divinity
Avenue, Cambridge, MA 02138, USA. 6
Informatics
Program, 7
Division of Newborn Medicine, 8
Division of
Neuroscience, Children’s Hospital, Boston, MA 02115,
USA.
*These authors contributed equally to this work.
.Present address: Molecular Neurobiology Laborato-
ry, The Salk Institute, 10010 North Torrey Pines Road,
La Jolla, CA 92037, USA.
-Present address: Department of Biology, Boston
College, 140 Commonwealth Avenue, Chestnut Hill,
MA 02467, USA.
`Present address: Department of Biological Sciences,
Rutgers University, 101 Warren Street, Newark, NJ
07102 USA.
¬To whom correspondence should be addressed. E-mail:
Qiufu_Ma@dfci.harvard.edu (Q.M.); Charles_Stiles@dfci.
harvard.edu (C.D.S.)
R E P O R T S
www.sciencemag.org SCIENCE VOL 306 24 DECEMBER 2004 2255
2. have been deposited at the American Type Cul-
ture Collection (ATCC) for open distribution.
We synthesized digoxigenin-labeled probes
for the TF-encoding genes. To visualize TF ex-
pression at an early developmental stage, we
analyzed the expression of 1013 TF-encoding
genes using whole-mount in situ hybridization
on E10.5 mouse embryos. Of these 1013, at
least 142 were clearly expressed in a spatially
restricted manner (table S6 and fig. S7). We
also performed in situ hybridization for 1034
TF genes on transverse sections through the
E13.5 and P0 head and trunk, as well as on
sections through the postnatal cerebellum at P7,
P15, and P21. Of 1034 genes examined in the
E13.5 and/or P0 nervous system, 349 showed
spatially restricted expression patterns (table
S3). For TFs that belong to non–zinc-finger
families, È38% of them showed restricted ex-
pression patterns in the CNS. However, only
È10% of zinc-finger genes showed restricted
patterns. Collectively, È27% of all the TFs ex-
hibited spatially restricted patterns (table S3).
We divided the CNS into seven general
areas for annotation: the cortex, striatum (and
other basal ganglia), thalamus, hypothalamus,
midbrain, hindbrain, and spinal cord. Very
few of the 349 TFs with spatially restricted
expression patterns were expressed in only
one region of the brain (table S4). Nearly all
TF-encoding genes expressed in the neonatal
brain were also detected in postmitotic
neurons at E13.5. Digital images of the entire
in situ hybridization set have been deposited
in the Mahoney Transcription Factor Atlas
(12), as well as in the Jackson Laboratory_s
Gene Expression Database (13).
The in situ hybridization data show that
postmitotic anatomical diversity within the
CNS can be described by TF expression. For
example, the neocortex is a highly laminated
and regionally organized anatomical struc-
ture (14). We found that several dozen TF-
encoding genes occupy different dorsoventral
positions or different laminae of the neocortex
(Fig. 1). In the striatum, a major basal ganglia
component crucial for movement control is
organized in a somatotopic fashion (15). This
somatotopic organization is echoed by the
gradient expression of many TF-encoding
genes in this area (fig. S1). The thalamus and
hypothalamus are organized into discrete ana-
tomical and functional nuclei that are marked
by the overlapping expression pattern of spe-
cific TFs within these regions (figs. S2 and
S3). In the retina, a large number of TF genes
are expressed with distinct density within the
retinal ganglion and amacrine cell layers (figs.
S4 and S5), which may correlate with the
morphological diversity of these cell types (1).
In the postnatal cerebellum, laminar-specific
TF expression marks the immature and mature
granule cells and Purkinje cells (fig. S6).
The genome-scale whole-mount and sec-
tion in situ hybridizations also identified over
100 TF genes expressed in spatially restricted
patterns within non-neuronal tissues such as
the nose, oral cavity, teeth, salivary gland,
inner ear bone, mandibular bone, eye muscle,
facial muscle, skin, and others (fig. S8 and
table S4). Although not the explicit focus of
this study, the open-source TF data set gener-
ated in this work provides detailed information,
enabling comprehensive study of developing
cranial facial tissues. The in situ plasmid set
provided here can be used to define TF expres-
sion patterns in other tissues and at other de-
velopmental times in neural tissues.
Our atlas of TF expression provides a
visual filter for functional analysis of the TF
gene set in brain development. Over 7% of the
murine genome may encode TFs. However,
our studies suggest that at a given developmen-
tal stage, fewer than 27% of these TF-encoding
genes are expressed in spatially restricted pat-
terns consistent with a direct role in the for-
mation of specific neural types. The regulatory
elements for these spatially restricted TFs might
be useful reagents for driving the expression of
reporter genes that will mark specific neural cell
types, as described recently by Gong et al. (16).
The TF expression profile in postmitotic neu-
rons will be useful to study the expression of
neural-specific genes encoding ion channels,
neurotransmitter receptors, and synaptic pro-
teins, whose molecular control remains largely
unknown. On a clinical front, TF mutations
Fig. 1. Diversity of transcription factor expression in the P0 mouse cerebral cortex. Nonradioactive
in situ hybridization patterns for 20 representative TFs or TF cofactors on sections through the
forebrain of P0 mice are shown. Labels at the bottoms of individual panels indicate Locuslink gene
names. (A) Over a dozen TF-encoding genes occupy different dorsoventral positions of the
hippocampus (top row) and neocortex (middle and bottom rows). (B) A dozen genes show laminar
specific expression in the neocortex. HC, hippocampus; BG, basal ganglia; SC, superior colliculus;
TH, thalamus; HY, hypothalamus; DG, hippocampal dentate gyrus; CA1 to 3, hippocampal CA1,
CA2, and CA3 regions. Scale bar in (A), 1 mm; all images in this section show the same
magnification. Scale bar in (B), 0.2 mm; all images in this section show the same magnification.
R E P O R T S
24 DECEMBER 2004 VOL 306 SCIENCE www.sciencemag.org2256
3. have already been shown to underlie certain
disorders in speech (17), appetite control (18),
breathing patterns (19), and autism (20) in hu-
mans. The TF atlas presented here may have
practical overtones for understanding addi-
tional neurological or behavioral disorders in
children and adults.
References and Notes
1. R. H. Masland, Curr. Biol. 14, R497 (2004).
2. R. Shirasaki, S. L. Pfaff, Annu. Rev. Neurosci. 25, 251
(2002).
3. E. L. Sonnhammer, S. R. Eddy, E. Birney, A. Bateman,
Nucleic Acids Res. 26, 320 (1998).
4. V. Matys et al., Nucleic Acids Res. 31, 374 (2003).
5. D. L. Wheeler et al., Nucleic Acids Res. 32, D35 (2004).
6. P. D. Thomas et al., Genome Res. 13, 2129 (2003).
7. D. Stryke et al., Nucleic Acids Res. 31, 278 (2003).
8. J. Hansen et al., Proc. Natl. Acad. Sci. U.S.A. 100,
9918 (2003).
9. R. H. Waterston et al., Nature 420, 520 (2002).
10. International Human Genome Sequencing Consorti-
um, Nature 431, 931 (2004).
11. N. M. Shah et al., Neuron 43, 313 (2004).
12. The Mahoney Transcription Factor Atlas is available
at http://mahoney.chip.org/mahoney/.
13. See the Jackson Laboratory’s Gene Expression Database,
accession no. J:91257, available at www.informatics.
jax.org/.
14. D. D. O’Leary, Y. Nakagawa, Curr. Opin. Neurobiol.
12, 14 (2002).
15. E. R. Kandel, J. H. Schwartz, T. M. Jessell, Principles of
Neural Science (McGraw-Hill, New York, 2000).
16. S. Gong et al., Nature 425, 917 (2003).
17. C. S. Lai, S. E. Fisher, J. A. Hurst, F. Vargha-Khadem,
A. P. Monaco, Nature 413, 519 (2001).
18. J. L. J. Holder, N. F. Butte, A. R. Zinn, Hum. Mol. Genet.
9, 101 (2000).
19. J. Amiel et al., Nature Genet. 33, 459 (2003).
20. N. Gharani, R. Benayed, V. Mancuso, L. M. Brzustowicz,
J. H. Millonig, Mol. Psychiatry 9, 474 (2004).
21. We thank J. Olsen, J. Chan, and P. Santos for their
technical assistance and R. DePinho for providing the
National Institute on Aging 15K cDNA set. We also
thank R. Segal and S. Pfaff for critical reading of this
manuscript. The work was supported by the Charles
Dana Foundation, the National Institute of Neuro-
logical Disorders and Stroke (Q.M., C.D.S., D.H.R., and
A.P.M.), the National Institute of Dental and Cranio-
factial Research (Q.M.), the National Institute of Dia-
betes and Digestive and Kidney Dieseases (A.P.M.), a
Ford Foundation Postdoctoral Fellowship for Minorities
(P.A.G.), a Parker B. Francis Fellowship in Pulmonary
Medicine (P.A.G.), and the Pew Trust (Q.M.).
Supporting Online Material
www.sciencemag.org/cgi/content/full/306/5705/2255/
DC1
Materials and Methods
Figs. S1 to S8
Tables S1 to S7
References
7 September 2004; accepted 15 November 2004
10.1126/science.1104935
Activity-Dependent Internalization
of Smoothened Mediated by
b-Arrestin 2 and GRK2
Wei Chen,1
* Xiu-Rong Ren,2
Christopher D. Nelson,2
Larry S. Barak,3
James K. Chen,4
. Philip A. Beachy,4
Frederic de Sauvage,5
Robert J. Lefkowitz2
*
Binding of Sonic Hedgehog (Shh) to Patched (Ptc) relieves the latter’s tonic
inhibition of Smoothened (Smo), a receptor that spans the cell membrane
seven times. This initiates signaling which, by unknown mechanisms,
regulates vertebrate developmental processes. We find that two molecules
interact with mammalian Smo in an activation-dependent manner: G protein–
coupled receptor kinase 2 (GRK2) leads to phosphorylation of Smo, and bbb-
arrestin 2 fused to green fluorescent protein interacts with Smo. These two
processes promote endocytosis of Smo in clathrin-coated pits. Ptc inhibits
association of bbb-arrestin 2 with Smo, and this inhibition is relieved in cells
treated with Shh. A Smo agonist stimulated and a Smo antagonist (cyclopamine)
inhibited both phosphorylation of Smo by GRK2 and interaction of bbb-arrestin 2
with Smo. bbb-Arrestin 2 and GRK2 are thus potential mediators of signaling by
activated Smo.
Hedgehog (Hh) signaling is mediated by
regulation of a protein called Smoothened
(Smo) that spans the cell membrane seven
times (7MS), activation of which sets in
motion transcriptional events that control
growth and patterning in vertebrate develop-
ment (1, 2). Dysregulated Smo activity also
leads to several forms of cancer (3–7). Hh
binds to a receptor that spans the cell mem-
brane 12 times, Patched (Ptc), and relieves
inhibitory control of Smo by Ptc. However,
almost nothing is known of the mechanisms
operating just downstream of Smo to medi-
ate and modulate its actions. b-Arrestins are
cytosolic proteins that bind to most acti-
vated 7MS receptors after the receptors
have been phosphorylated by GRKs, which
promotes internalization of the receptors
and some forms of signaling (8, 9). Elements
that regulate receptor functions often show
Table 1. Nonredundant numbers of putative TFs in the mouse genome. Columns describe the total
number of unique genomic loci encoding predicted DNA binding TFs by domain and the numbers and
relative percentages analyzed. The second to last column describes the number of family members
available as Genetrap cell lines in the Baygenomics and/or German Gene Trap Consortium libraries. The
last column describes the percentage of family members with available enhancer trap cell lines. Genes
that encode multiple DNA binding domains are listed and counted in one family for clarity. Nuclear
hormone receptors are not included in zinc-finger genes. Transcription cofactors and these non-TF genes
we analyzed are also included. Asterisks indicate the cofactor and non-TF gene numbers we analyzed
rather than the total number in the genome. HMG, high-mobility group; bZIP, basic helix-loop-helix and
leucine zipper proteins; non-TFs, genes that do not encode TFs; nuclear rec, nuclear hormone receptors;
ZF, zinc finger; ETS, erythroblast transformation–specific; PHD, plant homeodomain; btb/poz, broad-
complex, tramtrack, and bric-a-brac/poxvirus and zinc-finger proteins.
Domain No. of genes No. cloned % cloned Genetrap available % trapped
Homeobox 227 170 74.9 12 5.3
bHLH 116 100 86.2 22 19.0
HMG 58 41 70.7 14 24.1
bZIP 57 41 71.9 16 28.1
Nuclear Rec 50 46 92.0 10 20.0
Forkhead 40 29 72.5 12 30.0
ETS 28 26 92.9 8 28.6
ZF C2H2 490 287 58.6 171 34.9
ZF PHD 60 44 73.3 42 70.0
ZF C2CH 39 18 46.2 11 28.2
ZF btb/poz 28 18 64.3 8 28.6
Other 252 163 64.7 124 49.2
TF Total 1445 983 68.0 450 31.1
Cofactors* 133 104 78.2 48 36.1
Non-TFs* 336 261 77.7 95 28.6
Total genes 1914 1348 70.4 493 25.8
1
Department of Medicine, 2
Howard Hughes Medical
Institute, Departments of Medicine and Biochemistry,
3
Department of Cell Biology, Duke University Medical
Center, Durham, NC 27710, USA. 4
Howard Hughes
Medical Institute, Department of Molecular Biology
and Genetics, Johns Hopkins University School of Med-
icine, Baltimore, MD 21205, USA. 5
Department of Mo-
lecular Oncology, Genentech, South San Francisco, CA
94080, USA.
*To whom correspondence should be addressed.
E-mail: lefko001@receptor-biol.duke.edu (R.J.L.) and
w.chen@duke.edu (W.C.).
.Present address: Department of Molecular Pharma-
cology, Stanford University School of Medicine, Stan-
ford, CA 94305, USA
R E P O R T S
www.sciencemag.org SCIENCE VOL 306 24 DECEMBER 2004 2257