Several students asked: How is the gradient set up??
In the French flag model, the French flag is used to represent the effect of a morphogen on cell differentiation: a morphogen affects cell states based on concentration, these states are represented by the different colors of the French flag: high concentrations activate a "blue" gene, lower concentrations activate a "white" gene, with "red" serving as the default state in cells below the necessary concentration threshold.
If a pregnant woman does not have enough folic acid in her system during the first 4 weeks of pregnancy, the chance of neural tube defects is elevated.
most maternal pesticide exposure probably occurs through the diet, as is the case for the general U.S. population, but with additional residential non-dietary exposure most likely from ingress of pesticides from agricultural use into homes
Lecture4 psych125 bunge
PSYCH 125 Genetic & Environmental Influences on Early Brain Development
From last class: Patterning of the nervous system Concentration gradient(s) of signaling molecules known as morphogens Neural tubeThe morphogens activate varioustranscription factors in aspatially specific manner.These transcription factors bind tospecific sites in DNA sequence &“turn genes on/off”, patterning thenervous system
How is that gradient of signaling molecules set up??We’ll get there. First, some definitions: • Morphogen • Transcription and Translation of DNA • Transcription Factor
Morphogens• A signaling molecule that acts directly on cells to produce specific cellular responses dependent on morphogen concentration• French Flag Model by famous biologist Lewis Wolpert, 1960s: • High [ ] of morphogen activates blue gene • Medium [ ] activates white gene • Low [ ] is below threshold to activate either, and red is the default color Source: Wikipedia
Transcription factors• Also known as sequence-specific DNA-binding factors• A protein that controls gene transcription by binding to a specific DNA sequence (often within the promoter region of a gene)
But where do these gradients of morphogens comefrom?? Nobel Prizewinner Eric Wieschaus, Princeton talking about embryonic development in Drosophila http://www.youtube.com /watch?v=Ncxs21KEj0g The story begins before fertilization…
Source of protein gradients in theDrosophila oocyte1. mRNA molecules coming from the mother are anchored todifferent parts of the inside of the egg when it is first created.2. After fertilization, they produce protein, which diffuses along theanterior-posterior axis. So physical parameters like rate of diffusionhave important consequences for embryonic development!
Bicoid protein activates transcription factors in the headBicoid homologues are found in vertebrates
Sonic hedgehog (Ssh) a morphogen that organizes the neural tube along the dorsal-ventral axis in mammals
Hox genes produce developmental regulatoryproteins (transcription factors high in the chain ofcommand) that define regions within an embryo
Mutations in Hox genes could explain rapidevolutionary changes, e.g. from dinosaur to bird
Developmental Regulatory Genes (transcriptionfactors at the top of the chain of command) http://www.youtube.com/watch?
The full video is worth watching! http://www.youtube.com/watch? v=9sjwlxQ_6LI 1) EVO/DEVO - 00:51 2) Developmental Regulatory Genes - 2:00 3) Gap Genes - 2:39 4) Homeobox / HOX Genes - 2:50 5) Messed-Up Experiment - 6:16 6) EVO/DEVO & Evolution - 7:26 a) Chickens with teeth - 8:14
QuizPick the best definition of a transcription factor:A)A protein that acts directly on cells to produce specific cellular responsesdependent on morphogen concentrationB)A protein that defines regions within an embryoC)A protein that regulates gene expressionD)A protein that regulates the assembly of proteins from mRNA
Astonishing progress in genetics researchA is the hereditary materialquencing of human genome completed (< 60 yrs lat Francis S. Collins et al., Nature 422, 835-847(24 April 2003)
But genes aren’t everything… Venter, 1998: “Knowledge of the genes will change the future of humanity” Venter, 2010: “We have learned nothing from the human genome.”
Your phenotype is a product of your genotypeand your environment
Epigenetics“Nature vs. Nurture” is the wrong question…Of course, genes are important, but the environment regulates which genes areexpressed & when (epigenetics) Michael Meaney Megan Gunnar Charles Nelson III Nathan Fox
Origin of the term “epigenetics” Conrad Waddington coined the term “epigenetics” in 1942 to refer to a phenomenon that could not be explained by genetic principles: cellular differentiation (how can there be so many cell types in the body when they all share the same genetic material?) Goldberg, Allis, & Bernstein, Cell, 2007
Modern definition of epigenetics“Epigenetics, in a broad sense, is a bridge betweengenotype and phenotype—a phenomenon that changesthe final outcome of a locus or chromosome withoutchanging the underlying DNA sequence.”“More specifically, epigenetics may be defined as thestudy of any potentially stable and, ideally, heritablechange in gene expression or cellular phenotype thatoccurs without changes in Watson-Crick base-pairing ofDNA.” Goldberg, Allis, & Bernstein, Cell, 2007
Epigenetic influences on protein expression in neurons
Nutrients, toxins, stress hormones, etc. travel intofetal blood stream from the placenta
Epigenetic modifications can be transmitted to the 2nd generation! i.e., what you experience can affect your child…mothy G. Dinan, John Cryan, Fergus Shanahan, P. W. Napoleon Keeling & Eamonn M. M. Quigleyature Reviews Gastroenterology & Hepatology 7, 465-471
QuizWhich of the following statements about the phenomenon of epigenetics isFALSE?A) It alters whether/when a gene is expressed, and can even shut a gene offforeverB) It changes the base pair sequence that constitutes a geneC) It explains why identical twins have different phenotypesD) It explains how maternal stress could affect the developing fetus
Environmental causes of birth defects• Environmental factors only considered as contributing to abnormalities in 1940s; before that, assumed everything was hereditary.• N. Gregg discovered that German measles contracted by pregnant woman could cause abnormalities in fetus• In 1961, W. Lenz linked the sedative thalidomide to birth defects, making it clear that drugs could cross the placental barrier.• Since then, many agents have been identified as teratogens (factors that cause birth defects) 28
Sensitive period in embryonic development Sadler, TW (2010). Medical Embryology, Eleventh Edition.
Folic acid (Folate)Folate is a water-soluble B-vitamin.Our main food source is from leafygreen vegetables such as broccoli orspinach
Folate deficiency in utero linked to severelanguage delay at age 3• 40,000 children participating in the Norwegian Mother and Child Cohort Study. Children of mothers who used folic acid in the period four weeks before to eight weeks after conception had half the risk of having severe language delay at age three, compared to children of mothers who took no folic acid in this period (even if they took other vitamins)
More evidence linking folate to brain functioneven after early brain development Nilsson et al., Pediatrics, 2011
Folate and choline are linked metabolically, and both contribute to brain development & function B. C. A.A. Choline is acetylated to form acetylcholine, which is a growth factor for thedeveloping brain (as well as one of the main neurotransmitters in the brain, important forlearning & memory)B. Choline is phosphorylated and then used to form cellular membranes that arerequired for brain function.C. Choline is a methyl-group donor that – with folate – can influence DNA methylation andgene expression, which can, in turn, alter brain structure and function.
CholineCholine is a water-soluble essentialnutrient. Common food sources arewhole eggs and fatty meats.Vegetarians, vegans, endurance athletes, and people who drink a lot ofalcohol may be at risk for choline deficiency and may benefit from cholinesupplements. In general, people who do not eat many whole eggs may haveto pay close attention to get enough choline in their diets.
Choline: Striking effects in rodents• More choline (about 4x dietary levels) during days 11 to 17 of gestation in the rodent increases hippocampal progenitor cell proliferation, decreases apoptosis in these cells, enhances LTP in the offspring when they become adult animals, and enhances visuo-spatial and auditory memory by as much as 30% in the adult animals throughout their lifetimes.• Adult rodents exposed to extra choline in utero do not show decline in memory in old age!• Conclusion from research in rodents: during late pregnancy, when the hippocampus is developing, maternal dietary choline supplementation or deficiency is associated with significant and irreversible changes in hippocampal function, including altered long-term potentiation (LTP) and altered memory
Fetal Alcohol Syndrome Why would dysmorphology of the face be caus for concern? Facial tissue is derived from ectodermal tissue, which is the same tissue that gives rise to the brain…
Fetal alcohol exposure• Fetal alcohol exposure is the leading known cause of mental retardation in the Western world (Abel & Sokol, 1987 – from Wikipedia)• Overall incidence of alcohol-related problems is 1:100 live births• Fetal Alcohol Spectrum Disorder (FASD) is used to refer to any alcohol-related defects, whereas Fetal Alcohol Syndrome (FAS) represents the severe end of the spectrum and includes structural defects, growth deficiency, and mental retardation• Alcohol is worse for fetal brain development than cocaine!
QuizWhich of the following chemical compounds can travel through the umbilicalcord and influence fetal brain development?A)Stress hormones, alcohol, cocaine, nicotine, pesticides, etc.B)Choline, folate, and other nutrientsC)Neither A nor B: these compounds pass to the fetus from the placentaD)Both A and B
Policy Implications • The link between prenatal alcohol exposure and subsequent mental retardation and physical anomalies has been well-documented. • The lifetime medical and social costs of FAS are estimated to be as high as US $800,000 per child born with the disorder • The predominant policy response to this highly prevalent teratogen has focused largely on public education campaigns, cautionary signs in bars, and warning labels on bottles and cans. • What are the benefits and limitations of this kind of policy approach? • What other policy options are worthy of consideration, and how do they address potential conflicts between the rights of a pregnant woman to autonomy and the rights of a potential child to protection from harm? Slide courtesy of Charles Nelson III
Next class How did this baby’s brain development help him to become the famous 18-yr-old that he is today?