Genetics in Tooth Development
Introduction
The Molecular Program of Tooth Development
Primary Epithelial Band
Dental Lamina
Vestibular Lamina
Initiation of the Tooth
Genes expressed during tooth development
Developmental signals controlling the position and the number of tooth germs along the oral surface
Homeobox code model
Instructive Signals for Patterning
Tooth Type Determination
Regionalization of Oral and Dental Ectoderm
Bud Stage
Bud-to-Cap Transition
Signaling centres
Applied aspects
The initiation of tooth development begins at 37 days of development
with formation of a continuous horseshoe-band of thickened epithelium
in the location of upper and lower jaws – Primary Epithelial Band
Dental lamina appears as a thickening
of the oral epithelium adjacent to
condensation of ectomesenchyme
20 areas of enlargement or knobs
appear, which will form tooth buds
for the 20 primary teeth
Not all will appear at the same time.
The first to develop are those of the
anterior mandible region
At this early stage the tooth buds
have already determined their crown morphology
Successional lamina: lamina from
which permanent teeth develop
The dental lamina begins to function
at 6th prenatal week and continues to
15th year of birth (3rd molar)
Tooth development is a continuous process, however can be
divided into 3 stages:
1. Bud Stage
2. Cap Stage
3. Bell Stage
4. Hertwigs epithelial root sheath and root formation
The bud stage is represented by the first epithelial incursion into the ectomesenchyme of the jaw.
The epithelial cells show little if any change in shape or function.
The supporting ectomesenchymal cells are packed closely beneath and around the epithelial bud. As the epithelial bud continues to proliferate into the ectomesenchyme, cellular density increases immediately adjacent to the epithelial outgrowth.
This process is classically referred to as a condensation of the ectomesenchyme.
The epithelium of the dental lamina separated from the underlying ectomesenchyme by basement membrane.
Bud stage is characterized by rounded, localized growth of
epithelium surrounded by proliferating mesenchymal cells,which are packed closely beneath and around the epithelial buds
The transition from bud to cap marks the onset of morphologic differences between tooth germs that give rise to different types of teeth.
Differential cellular division in the epithelial bud initiates a change in shape so that now the epithelial outgrowth assumes a more complex outline with a flattened internal portion along which the mesenchymal condensation densifies.
As the tooth bud grows larger, it drags along with it part of the dental lamina; thus from that point on, the developing tooth is tethered to the dental lamina by an extension called the lateral lamina.
At this early stage of tooth development, identifying the formative elements of the tooth and its supporting tissues is already possible.
The epithelial outgrowth, which superficially resembles a cap sitting on a ball of condensed ectomesenchyme , is still referred to widely as the dental organ but actually should be called the enamel organ, because it eventually will form the enamel of the tooth. Henceforth, the term enamel organ is used.
Condensation of the ectomesenchyme immediately subjacent to the tooth bud caused by lack of extracellular matrix secretion by the cells thus preventing separation.
The initiation of tooth development begins at 37 days of development
with formation of a continuous horseshoe-band of thickened epithelium
in the location of upper and lower jaws – Primary Epithelial Band
Dental lamina appears as a thickening
of the oral epithelium adjacent to
condensation of ectomesenchyme
20 areas of enlargement or knobs
appear, which will form tooth buds
for the 20 primary teeth
Not all will appear at the same time.
The first to develop are those of the
anterior mandible region
At this early stage the tooth buds
have already determined their crown morphology
Successional lamina: lamina from
which permanent teeth develop
The dental lamina begins to function
at 6th prenatal week and continues to
15th year of birth (3rd molar)
Tooth development is a continuous process, however can be
divided into 3 stages:
1. Bud Stage
2. Cap Stage
3. Bell Stage
4. Hertwigs epithelial root sheath and root formation
The bud stage is represented by the first epithelial incursion into the ectomesenchyme of the jaw.
The epithelial cells show little if any change in shape or function.
The supporting ectomesenchymal cells are packed closely beneath and around the epithelial bud. As the epithelial bud continues to proliferate into the ectomesenchyme, cellular density increases immediately adjacent to the epithelial outgrowth.
This process is classically referred to as a condensation of the ectomesenchyme.
The epithelium of the dental lamina separated from the underlying ectomesenchyme by basement membrane.
Bud stage is characterized by rounded, localized growth of
epithelium surrounded by proliferating mesenchymal cells,which are packed closely beneath and around the epithelial buds
The transition from bud to cap marks the onset of morphologic differences between tooth germs that give rise to different types of teeth.
Differential cellular division in the epithelial bud initiates a change in shape so that now the epithelial outgrowth assumes a more complex outline with a flattened internal portion along which the mesenchymal condensation densifies.
As the tooth bud grows larger, it drags along with it part of the dental lamina; thus from that point on, the developing tooth is tethered to the dental lamina by an extension called the lateral lamina.
At this early stage of tooth development, identifying the formative elements of the tooth and its supporting tissues is already possible.
The epithelial outgrowth, which superficially resembles a cap sitting on a ball of condensed ectomesenchyme , is still referred to widely as the dental organ but actually should be called the enamel organ, because it eventually will form the enamel of the tooth. Henceforth, the term enamel organ is used.
Condensation of the ectomesenchyme immediately subjacent to the tooth bud caused by lack of extracellular matrix secretion by the cells thus preventing separation.
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PHYSICAL PROPERTIES
CHEMICAL PROPERTIES
STRUCTURE OF ENAMEL
DEVELOPMENT OF ENAMEL
EPITHELIAL ENAMEL ORGAN
AMELOGENESIS
LIFE CYCLE OF AMELOBLASTS
AGE CHANGES IN ENAMEL
DEFECTS OF AMELOGENESIS
CLINICAL IMPLICATIONS
Central face begins to develop by 4th week, when olfactory placodes appear on both sides of the frontonasal process.
Gradually both placodes develop to form the median and lateral nasal process.
Upper lip is formed by 6th week by fusion of two median nasal processes in midline and the maxilllary process of the 1st branchial arch.
PRE-NATAL GROWTH AND DEVELOPMENT OF PALATEFormation of primary and secondary palate
Elevation of palatal shelves
Fusion of palatal shelves
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PHYSICAL PROPERTIES
CHEMICAL PROPERTIES
STRUCTURE OF ENAMEL
DEVELOPMENT OF ENAMEL
EPITHELIAL ENAMEL ORGAN
AMELOGENESIS
LIFE CYCLE OF AMELOBLASTS
AGE CHANGES IN ENAMEL
DEFECTS OF AMELOGENESIS
CLINICAL IMPLICATIONS
Central face begins to develop by 4th week, when olfactory placodes appear on both sides of the frontonasal process.
Gradually both placodes develop to form the median and lateral nasal process.
Upper lip is formed by 6th week by fusion of two median nasal processes in midline and the maxilllary process of the 1st branchial arch.
PRE-NATAL GROWTH AND DEVELOPMENT OF PALATEFormation of primary and secondary palate
Elevation of palatal shelves
Fusion of palatal shelves
Dental anomalies are caused by complex multifactorial interactions between genetic, epigenetic and environmental factors during the long process of dental development.
This process is multilevel, multidimensional and progressive. It involves multiple interactions and critical stages
Dental anomalies are caused by complex multifactorial interactions between genetic, epigenetic and environmental factors during the long process of dental development.
This process is multilevel, multidimensional and progressive. It involves multiple interactions and critical stages
IOSR Journal of Dental and Medical Sciences is one of the speciality Journal in Dental Science and Medical Science published by International Organization of Scientific Research (IOSR). The Journal publishes papers of the highest scientific merit and widest possible scope work in all areas related to medical and dental science. The Journal welcome review articles, leading medical and clinical research articles, technical notes, case reports and others.
Tooth agenesis is one of the most common congenital malformations in humans. Hypodontia can either occur as an isolated condition (non-syndromic hypodontia) or can be associated with a syndrome (syndromic hypodontia), highlighting the heterogeneity of the condition. Gene anomalies or mutations in MSX1, PAX9, AXIN2 and EDA genes, appear to be most critical during the development of tooth, leading to various forms of tooth agenesis and systemic features. The aim of this paper is to review the genetic basis of hypodontia and identify the genes that have been definitively implicated in the agenesis of human dentition.
Epithelial – Mesenchymal Interactions in Tooth Development.pptxDrPurvaPihulkar
Epithelial mesenchymal interactions (EMIs) are a series of programmed, sequential and reciprocal (complex and multiphase) communications between the epithelium and the mesenchyme with its heterotypic cell population, that result in the differentiation of one or both cell populations.
Odontogenesis is the process of tooth development, which involves both ectodermal and mesenchymal components, being the key elements in the development of teeth.
In order for the tooth to form, an interactive mechanism between these heterotypic cellular populations is required.
For these interactions to occur there should be some or other form of messenger system between epithelium and mesenchyme, further underlining the importance of cell signaling networks and intricacies of physiological growth of an individual.
In the process of embryonic development the ectoderm is composed of surface ectoderm, neural crest and neural tube.
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Lymphomas are primary malignancies of lymph nodes and the peripheral lymphatics.
Neoplastic proliferative process of the lymphopoietic portion of the lymphoid system that involves cells of either the lymphocytic or histiocytic series in varying degrees of differentiation & occurs in an essentially homogenous population of a single cell type.
The first lymphoma type recognised was by Dr Thomas Hodgkin in 1832. In 1865 Dr Samuel Wilks recognised additional cases, rediscovered the report by Hodgkin, and designated this neoplasm as ‘Hodgkin disease’.
Hodgkin lymphoma (HL) represents about 10% of all lymphomas.
HL is distinct from other non-Hodgkin lymphomas, clinically by the contiguous spread of tumour along the lymphoid system, and morphologically by the presence of a spectrum of neoplastic cells, including mononuclear Hodgkin (H) cells, classic multinucleated Reed–Sternberg (RS) cells, and mummified (degenerating) cells against an inflammatory background.
The background inflammatory cells actively attracted by HL tumour cells may include T cells, B cells, histiocytes, plasma cells, neutrophils, eosinophils and mast cells.
The etiology of HD is unknown. Infectious agents, especially the Epstein-Barr virus (EBV), may be involved in the pathogenesis.
In as many as 50% of HD cases, the tumor cells are EBV-positive. EBV positivity is higher with mixed cellularity Hodgkin disease (60–70%) than the nodular sclerosis Hodgkin disease (15–30%).
Epstein–Barr virus (EBV), also called human herpes virus 4 (HHV-4), is a member of the herpes family and is one of the most common viruses in humans.
In immunocompetent hosts, EBV-infected B cells are in a resting state under host T-cell immune surveillance.
In hosts with immune dysfunction, EBV-infected cells in the reservoir may be reactivated and proliferate.
In EBV-infected cells, based on the viral proteins expressed, three latency transcription programs of EBV are designated: growth program (latency III) with expression of EBV nuclear antigens 1–6 (EBNA1-6), latent membrane proteins (LMP1, 2A and 2B); default program (latency II) expressing EBNA1, LMP1 and LMP2A; and latency program (latency I), with none or only expression of LMP2A.
In EBV-positive cases, usually all HRS cells are positive, indicating that the infection was an early event in lymphoma development.
The EBV+ HRS cells typically show an EBV latency II gene expression profile, meaning expression of the viral proteins EBV nuclear antigen 1 (EBNA1) and latent membrane proteins 1 and 2a (LMP1 and LMP2a).
EBNA1 is essential for replication of the episomal viral genome in proliferating cells. LMP1 mimics an active CD40 receptor and hence stimulates NF- B and PI3K/AKT activity.
As BCR and CD40 signalling are main survival signals for GC B cells, EBV infection of GC B cells may be a way how GC B cells with destructive mutations survive and become HRS precursor cells.
The non-Hodgkin lymphomas include a diverse and complex group of malignancies of lymphoreticular histogenesis and differentiation.
In most instances, they initially arise within lymph nodes and tend to grow as solid masses.
The non-Hodgkin lymphomas most commonly originate from cells of the B-lymphocyte series, with an estimated 85% of European and American lymphoid neoplasms having this derivation.
Tumors with a T-lymphocyte derivation are less common, whereas true histiocyte-derived lymphomas are even rarer.
Genetic abnormalities like nonrandom chromosomal and molecular rearrangements play an important role in the pathogenesis of many lymphomas and correlate with histology and immunophenotype.
Most lymphomas do not have a familial pattern; however, coexistence of multiple breast cancers, ovarian cancer, sarcomas, and lymphomas in a family may suggest an inherited abnormality in tumor suppressor genes.
Environmental factors also seem to play a role in the development of NHL. Certain chemicals have been linked to the development of NHL include a variety of pesticides and herbicides (e.g. organophosphates, chlorophenols), solvents and organic chemicals (e.g. benzene, carbon tetrachloride), and wood preservatives.
Thus certain workers like pesticide applicators, workers in the petroleum, rubber, plastics, and synthetic industries have a slightly increased risk of NHL.
Patients who receive cancer chemotherapy and/or radiation therapy are at increased risk of developing NHL.
Several viruses have been implicated in the pathogenesis of NHL, including the Epstein-Barr virus in Burkitt’s lymphoma (especially in endemic areas of Africa), sinonasal lymphoma in Asia and South America, and lymphomas in immunocompromised patients; HTLV-1 Human T-lymphotropic Virus in adult T-cell lymphoma/leukemia; and human herpesvirus 8 (HHV 8) in body cavity-based lymphomas in patients with HIV infection.
Immunodeficiency states that seem to predispose to NHL include congenital immunodeficiency states (e.g. ataxia telangiectasia, Wiskott–Aldrich syndrome, common variable hypogammaglobulinemia, severe combined immunodeficiency (SCID) as well as acquired immunodeficiency states (e.g. HIV infection, iatrogenic immunosuppression for solid organ or bone marrow transplant recipients).
Connective-tissue disorders, including Sjögren syndrome, rheumatoid arthritis, chronic lymphocytic thyroiditis, and systemic lupus erythematosus (SLE) are also associated with increased risk of NHL.
The microscopic appearance of the lesional cells was used in the past to classify the tumors as either lymphocytic or histiocytic.
With the development of modern immunologic techniques, however, it is now known that many of the lesions that had been classified as histiocytic were in fact neoplasms composed of transformed B lymphocytes. In the early 1980s, a group of American pathologists devised a classification scheme, known as the Working Formulation for Clinical Use.
S. mutans was originally isolated from carious human teeth by Clarke in 1924.
Little attention was paid to this species until the 1960s when it was demonstrated that caries could be experimentally-induced and transmitted in animals artificially-infected with strains resembling S. mutans.
Besides functioning as a resistant structural matrix, insoluble extracellular polysaccharides can act as a diffusion barrier.
The transport of metabolites and salivary buffers into the plaque and the diffusion of acid out of the plaque may be affected by glucan.
Fructans, on the other hand, unlike the mutan homopolymer of glucan, are generally soluble and can be degraded by plaque bacteria, thus serving as a reservoir of fermentable sugars for oral bacteria.
A group of fructans produced by bacteria or created by breaking down other kinds of plant fructans are called levan .
Levans are both more soluble and more readily catabolized than glucans.
Since levan hydrolysis is rapid, it may function as a short-term reservoir for the sustenance of bacterial anaerobic glycolysis in times of relative unavailability of dietary carbohydrate.
Lipoteichoic acid is another extracellular polymer that is found in cultures of S. mutans. These highly negatively charged compounds might contribute to the adhesiveness of bacteria.
In addition to this, S. mutans strains have an ability to store intracellular glycogen amylopectin type polysaccharide, which provides a reservoir of substrate and enables prolonged periods of increased metabolic activity.
Intracellular glycogen and extracellular polysaccharides serve as substrate reservoirs, which the organism may utilize for energy production, as the exogenous supplies of readily metabolized carbohydrate are depleted. In this fashion, both types of polysaccharides may play a role in the survival of organisms and in their potential to prolong acid production via glycolysis well beyond meal time.
It is known that sucrose-adapted S. mutans strains possess significant levels of invertase activity, and this enzyme isknown to hydrolyze sucrose intracellularly to free glucose and fructose.
Invertase is activated by inorganic phosphate and since phosphate accumulation is coupled with acid production, it is probable that one of the several mechanisms by which sucrose degradation is regulated in S. mutans is the activation of invertase by inorganic phosphate.
Cariogenic features of mutans streptococci - Binding to and colonization of teeth
Accumulation on tooth surfaces & participation in the formation of dental plaque.
Production of acid at a high rate.
Tolerance of high concentration of sugar, high ionic strength & highly acidic conditions
Association with dental caries in humans
Causation of dental caries in animals
Transmissible in animals & apparently in man
Reduction or elimination of mutans results in reduction or elimination of dental caries
Sterilization
It is defined as the process by which an article, surface or medium is freed of all living microorganisms either in vegetative or spore state.
Disinfection
It is destruction or removal of all pathogenic organisms or organisms capable of producing infections but not necessarily spores.
DISEASES OF NERVES AND MUSCLES
Pain is defined as an “unpleasant sensory and emotional
experience that is associated with actual or potential
tissue damage, or described in such terms even in the
absence of any obvious damage.”
Nociceptive pain
on the one hand, is caused by actual tissue injury and inflammation, such as seen with pulpal involvement of a tooth secondary to dental caries, and is an important physiological protective mechanism
Neuropathic pain
on the other hand, is caused by dysfunction of the central and/or peripheral nervous system in the absence of active injury or inflammation, such as post-herpetic neuralgia, that results in neurosensory signs and symptom
CLSSIFICATION
Trigeminal neuralgia
Glossopharyngeal neuralgia
Sphenopalatine ganglion neuralgia
Raeder’s paratrigeminal
Atypical pain/neuralgia
Postherpetic facial neuralgia
Migrainous neuralgia
Occipital neuralgia
Geniculate neuralgia
Superior laryngeal neuralgia
Tympanic plexus neuralgia
Trigeminal neuralgia –Etiology
Dental pathosis—dental pathosis is believed by some investigators to be involved with the onset of trigeminal neuralgia.
Excessive traction—secondary to excessive traction on the various divisions of the fifth nerve, being influenced by maxillo-mandibular relationship.
3 .• Allergic—it can be secondary to an allergic and hypersensitivity reaction causing edema of the trigeminal nerve root.
4• Ischemia—Wolf thought that ischemia at various portions of the trigeminal pathway might be responsible for the paroxysms of pain.
5. Compression distortion phenomenon—Jannetta and others have shown subtle changes of a compression- distortion phenomenon which is usually caused by arterial loops of atherosclerotic vessels. Vessels become elongated with advancing age and withatherosclerotic involvement gain abnormal positions by wedging into the spacebetween the pons and trigeminal nerve. It is postulated that with progressive material elongation, fascicles of adjacent nerves later suffer myelin injury and pain results.
6• Mechanical factors—like pressure due to aneurysms of the intrapetrous portion of the internal carotid artery that may erode through the floor of the intracranial fossa to exert a pulsatile irritation on the ventral side of the trigeminal ganglion.
7• Anomalies of superior cerebellar artery—it is the most recently blamed cause for trigeminal neuralgia. It lies in contact with the sensory root of the nerve and implicated as a cause of demyelination. Surgical elevation of artery or decompression of the sensory root has high success rate in relieving paroxysmal pain in case of idiopathic trigeminal neuralgia.
8• Secondary lesion—conditions such as carcinoma of the maxillary antrum, nasopharyngeal carcinoma, tumors of peripheral nerve root, intracranial vascular anomalies,and multiple sclerosis may be presented with trigeminal pain.
2.Glossopharyngeal neuralgia
The most common causes of glossopharyngeal neuralgia are
intracranial or extracranial
MANDIBULAR LATERAL INCISOR
INTRODUCTION
Lateral incisors generally appear in the oral cavity after central incisors.
Lateral incisors usually erupts during the seventh year of life .
Roots complete: 9 – 10 years
FDI SYSTEM (Federation Dentaire Internationalae)-
Mandibular RIGHT lateral incisor- 42
Mandibular LEFT lateral incisor- 32
UNIVERSAL SYSTEM-
Mandibular RIGHT lateral incisor- 26
Mandibular LEFT lateral incisor- 23
Zsigmondy-palmar system
Mandibular RIGHT central incisor-
2
Mandibular LEFT central incisor-
2
ARCH TRAITS
Lingual fossa are less pronounced on mandibular incisors.
Mandibular lateral incisors have roots that are more triangular in cross section.
Labio-lingual diameter is wider than mesio-distal diameter.
CLASS TRAITS-
Crown shapes are rectangular, longer inciso-gingivally than mesio-distally.
Mesial & distal marginal ridge converge toward the lingual cingulum.
SET TRAIT
There are depression or perikymata on the labial surface of the crown of the incisors.
Mammelons are seen on the incisal edge of newly erupted incisors.
Cervical ridges of anterior permanant teeth are prominent than primary teeth.
TYPE TRAIT
Lateral incisors have distal proximal contact more apical than the mesial contact.
Lateral incisors have disto-incisal angle more rounded than the mesio-incisal angle.
Labial Aspect
Crown is trapezoidal from labial aspect.
Mesial outline is almost straight in line with mesial outline of root.
Distal outline is straight near cervix and become slightly convex as it reaches distoincisal angle.
Distoincisal angle more rounded than mesioincisal angle
Incisal outline formed by incisal ridge is straight but has tendency to slope cervically in distal direction.
Cervical line is curved apically.
Crown is not bilaterally symmetrical
Distal half is slightly larger.
lingual aspect
Its shape is trapezoidal like labial surface.
Crown tapers lingually making lingual surface narrower than labial surface.
Shallow lingual fossa
Lingual surface is smooth devioid of developmental grooves, and is convex near cingulum.
Distal surface bulges from the incisal view
incisal aspect
It is oval labiolingually.
Labiolingual dimension is greater than mesiodistal.
Incisal ridge is at an angle to the line bisecting the tooth labiolingually rather than being perpendicular.
Slightly twisted on its root base from this aspect.
Cingulum twisted (off-center) to the distal
mesial aspect
Mesial aspect is triangular
Labial outline is convex near cervical line
Lingual outline is straight in incisal 3rd
Incisal edge lingual to root axis line
CEJ is curved more on the mesial than the distal
Mesial contact area is at incisal 3rd of crown
Mesial surface is longer than distal surface
developmental disturbances of teeth
DEVELOPMENTAL DISTURBANCES IN NUMBER OF TEETH
DEVELOPMENTAL DISTURBANCES IN SIZE OF TEETH
DEVELOPMENTAL DISTURBANCES IN SHAPE OF TEETH
Anodontia
Supernumerary teeth
Predeciduous dentition
Post permanent dentition
Microdontia
Macrodontia
Gemination
Fusion
Concrescence
Dilaceration
Talon cusp
Taurodontism
Supernumerary roots
DEVELOPMENTAL DISTURBANCES OF GINGIVA
1) Fibromatosis Gingivae(Elephantiasis gingivae, hereditary gingival fibromatosis, congenital macrogingivae)
Fibromatosis gingivae is a diffuse fibrous overgrowth of the gingival tissues.
This condition is manifested as a dense, diffuse, smooth, or nodular overgrowth of the gingival tissues of one or both arches, usually appearing about the time of eruption of the permanent incisors.
Even seen in very young children
It is not painful and shows no tendency for hemorrhage.
The extent of the tissue overgrowth may be such that the crowns of the teeth are nearly hidden even though they are fully erupted with respect to the alveolar bone .
2) Retrocuspid Papilla
It is a small, elevated nodule located on the lingual mucosa of the mandibular cuspids.
Clinical Features
This soft, well-circumscribed, sessile, mucosal nodule, commonly bilateral, is located lingual to the mandibular cuspid, between the free gingival margin and the mucogingival junction.
It is exceedingly common in children.
Found a greater occurrence bilaterally than unilaterally.
The structure appears as an elevated mucosal tag often showing mild hyperorthokeratosis or hyperparakeratosis, with or without acanthosis.
The underlying connective tissue is sometimes highly vascularized and may exhibit large stellate fibroblasts as well as occasional epithelial rests.
Because of its frequency of occurrence, the retrocuspid papilla is often considered to be a ‘normal’ anatomic structure which regresses with age and requires no treatment.
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
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Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
2. INDEX
Introduction
The Molecular Program of Tooth Development
Primary Epithelial Band
Dental Lamina
Vestibular Lamina
Initiation of the Tooth
Genes expressed during tooth development
Developmental signals controlling the position and
the number of tooth germs along the oral surface
3. Homeobox code model
Instructive Signals for Patterning
Tooth Type Determination
Regionalization of Oral and Dental Ectoderm
Bud Stage
Bud-to-Cap Transition
Signaling centres
Applied aspects
4. INTRODUCTION
Teeth, like all epithelial appendages, form via a
sequential and reciprocal series of inductive signals
transmitted between the epithelium and neural crest
derived mesenchyme.
Each tissue layer instructs the other to differentiate in a
precisely determined manner leading to the formation of
highly specialized structures, such as incisors, canines,
premolars and molars.
Each of these groups of teeth derives from different parts
of the oral epithelium and, depending on the species,
teeth can be formed from both endoderm and ectoderm
or from ectoderm only
5. Animal and human studies that employ the tools of
contemporary molecular genetics have identified a
number of genes that act at specific stages of tooth
development and regulate its patterning and
differentiation process
6. However, to better understand morphogenesis, the
molecular signals that control cell growth, migration,
and ultimately cell fate and differentiation also must
be considered.
7. The molecular aspect of tooth development is
interesting in that it shares many similarities with the
development of a number of other organs (e.g., lung
and kidney) and that of the limbs.
Thus the tooth organ represents an advantageous
system in which to study not only its own
development but also developmental pathways, in
general
8. The five major conserved signaling pathways that
intervene in these events are
(1) Bone morphogenetic protein (BMP)
(2) Fibroblast growth factor, (FgF)
(3) Sonic hedgehog (Shh)
(4) Wingless-related integration site (Wnt)
(5) Ectodysplasin A (Eda).
9. The Molecular Program of Tooth
Development
The signaling molecules mediating communication
between cells constitute one of the key groups of
molecules in this conserved toolbox.
There are four major families of signal molecules
that are essential for cell communication in all
animals from flies to man as well as in all different
organs, including teeth.
These are BMP (bone morphogenetic protein), FGF
(fibroblast growth factor), hedgehog, and Wnt
10. In addition, ectodysplasin (Eda), an NFkB family
signal, plays key roles in the development of teeth
and other ectodermal appendages.
The signals can be thought to constitute the
“language” of interacting cells, and they regulate
tooth development all the way from initiation to root
formation
11. The toolbox also includes receptors for signals at the
cell surface, mediators transmitting the signal in
the cell, and transcription factors regulating gene
expression in the nucleus.
The transcription factors are of special importance
because they regulate the fate of cells.
12. In particular, specific combinations of transcription
factors can determine the identities of different cell
types. Knowledge of such transcription factor codes
is essential for cellular reprogramming in
regeneration studies.
However, so far the “transcription factor codes” of
tooth- specific cells are not known.
13. The reciprocal and sequential interactions between
dental mesenchyme and epithelium constitute the
core of the molecular program.
The interactions are mediated by the conserved
signal molecules activating the expression of
specific transcription factors, which in turn
regulate the expression of numerous other genes
important for advancing morphogenesis and cell
differentiation in the developing tooth.
14.
15. Primary Epithelial Band
After about 37 days of development, a continuous
band of odontogenic epithelium forms around the
mouth in the presumptive upper and lower jaws.
These bands are roughly horseshoe-shaped and
correspond in position to the future dental arches of
the upper and lower jaws
16. A key feature of the initiation of tooth development is
the formation of localized thickenings or placodes
within the primary epithelial bands.
Dental placodes are believed to initiate formation of
the various tooth families.
17.
18. The basic mechanisms and genes involved in the
formation and function of all placodes are similar.
The balance between stimulatory (FGFs, Wnts)
and inhibitory signals (BMPs) is important in
determining the site of placodes
19. Formation and growth of placodes is believed to
involve the transcription factor p63, tumor
necrosis factor (TNF), and ectodysplasin (Eda).
20. Dental Lamina
On the anterior aspect of the down-growing dental
lamina, continued and localized proliferative activity
leads to the formation of a series of epithelial
outgrowths into the mesenchyme at sites
corresponding to the positions of the future
deciduous teeth
21. Ectomesenchymal cells accumulate around these
outgrowths.
From this point, tooth development proceeds in
three stages: the bud, cap, and bell.
23. Vestibular Lamina
The vestibule forms as a result of the proliferation of
the vestibular lamina into the ectomesenchyme
soon after formation of the dental lamina.
The cells of the vestibular lamina rapidly enlarge and
then degenerate to form a cleft that becomes the
vestibule between the cheek and the tooth-bearing
area
24. Initiation of the Tooth
Odontogenesis is initiated first by factors resident in
the first arch epithelium influencing
ectomesenchyme but that with time this potential is
transferred to and is assumed by the
ectomesenchyme
These experimental findings are mirrored by the
expression pattern of transcription and growth
factors in these tissues.
26. The earliest histologic indication of tooth
development is marked by a thickening of the
epithelium where tooth formation will occur on the
oral surface of the first branchial arch
The genes that are implicated in the ensuing
To date, the earliest mesenchymal markers for tooth
formation are the LIM-homeobox (Lhx) domain
genes (transcription factors), Lhx-6 and Lhx-7
27.
28. Both of these genes are expressed in the neural
crest–derived ectomesenchyme of the oral portion of
the first branchial arch as early as day 9 of
gestation
Experimental data demonstrate that the expression
of Lhx-6 and Lhx-7 results from a signaling
molecule originating from the oral epithelium of the
first branchial arch.
29. If second arch mesenchyme is recombined with first
branchial arch oral epithelium, Lhx-6 and Lhx-7 will
be induced.
However, if first branchial arch mesenchyme (which
expresses Lhx-6 and Lhx-7) is recombined with
second branchial arch epithelium, expression of both
genes will be downregulated quickly
30. A prime candidate for the induction of Lhx genes is
secreted fibroblast growth factor-8 (Fgf-8); this
growth factor is expressed at the proper place and
time in the first branchial arch and is able to induce
Lhx-6 and Lhx-7 expression .
32. In terms of developmental signals , What
controls the position and the number of
tooth germs along the oral surface?
The Pax-9 gene is one of the earliest mesenchymal
genes that define the localization of the tooth
germs.
Pax-9 gene expression colocalizes with the exact
sites where tooth germs appear.
Pax-9 is induced by Fgf-8 and is repressed by
bone morphogenetic proteins (BMP-2 and BMP-4).
33. Fgf-8, Bmp-2, and Bmp-4 are expressed in
nonoverlapping areas, with Pax-9 being expressed
at sites where Fgf-8 is but Bmp is not.
Number of other genes are also expressed in oral
epithelium at the same time.
Whether they directly regulate the expression of
Fgf-8 or Bmps is not clear at this time.
34. Little is known about the regulatory mechanisms of
signaling molecules, and untangling the network of
regulatory events can be difficult.
At least 12 transcription factors are expressed in
odontogenic mesenchyme, and some have
redundant roles.
To date, more than 90 genes have been identified
from the oral epithelium, dental epithelium, and
dental mesenchyme during the initiation of tooth
development.
35. In mice, expression of Shh is localized to the
presumptive dental ectoderm at E11 and is thus
another good signaling candidate for tooth initiation .
Mutations in Gli genes that are downstream
mediators of Shh action suggest a role in early tooth
development, because Gli2−/− and Gli3−/− double
mutant embryos do not produce any recognizable
tooth buds.
36.
37. Addition of Shh-soaked beads to oral ectoderm can
induce local epithelial cell proliferation to produce
invaginations that are reminiscent of tooth buds.
Shh thus appears to have a role in stimulating
epithelial cell proliferation, and its local expression at
the sites of tooth development implicates Shh
signaling in tooth initiation
38. Cbfa1, also referred to as Osf2, is a transcription
factor that plays a critical role during bone formation
.
Its expression in dental mesenchyme is associated
with the early signaling cascades regulating tooth
initiation.
It regulates key epithelial–mesenchymal
interactions that control advancing morphogenesis
and histodifferentiation of the enamel organ.
39. Paired like homeodomain transcription factor 2 (Pitx-
2) is a key player in pattern formation and cell fate
determination during embryonic development.
Pitx-2 is one of the earliest markers of tooth
development and continues to be expressed through
crown formation.
40. It regulates early signaling molecules and
transcription factors necessary for tooth
development.
Another factor is Lef-1, a member of the high-
mobility group family of nuclear proteins that
includes the T-cell factor proteins, known to be
nuclear mediators of Wnt signaling.
41. Lef-1 is first expressed in dental epithelial
thickenings and during bud formation shifts to being
expressed in the condensing mesenchyme.
Expression of several genes in ectomesenchyme
marks the sites of tooth germ initiation.
These include Pax-9 and Activin-A, both of which are
expressed beginning around E11 in mice within small
localized groups of cells corresponding to where
tooth epithelium will form buds
42. In the case of Pax-9, antagonistic interactions
between Fgf-8 and Bmp-4, similar to those found to
regulate Barx-1 expression, from oral ectoderm have
been shown also possibly to act to localize Pax-9
expression.
44. The determination of specific tooth types at their
correct positions in the jaws is referred to as
patterning of the dentition.
The determination of crown pattern is a remarkably
consistent process
Two hypothetical models—the field and clone
models —have been proposed to explain how these
different shapes are determined, and evidence exists
to support both
45.
46. The field model proposes that the factors responsible for
tooth shape reside within the ectomesenchyme in distinct
graded and overlapping fields for each tooth family
The fact that each of the fields expresses differing
combinations of patterning homeobox genes supports
this theory.
The The homeobox code (field) model for dental
patterning is based on observations of the spatially
restricted expression of several homeobox genes in the
jaw primordial ectomesenchyme cells before E11.
47. The early expression of Msx-1 and Msx-2 homeobox
genes before the initiation of tooth germs is
restricted to distal, midline ectomesenchyme in
regions where incisors (and canines in human
beings), but not multicuspid teeth, will develop,
whereas Dlx-1 and Dlx-2 are expressed in
ectomesenchyme cells where multicuspid teeth, but
not incisors (or canines), will develop.
48. Expression of Barx-1 overlaps with Dlx-1 and Dlx-
2 and corresponds closely to ectomesenchymal cells
that will develop into molars
The homeobox code model thus proposes that the
overlapping domains of the previously mentioned
genes provide the positional information for tooth
type morphogenesis
49. Support for this model comes from the dental
phenotype of Dlx-1−/− and Dlx2−/− double-knockout
mice in which development of maxillary molar teeth
is arrested at the epithelial thickening stage.
As predicted by the code model, incisor development
is normal in these mice; normal development of
mandibular molars (not predicted by the code)
results from functional redundancy with other Dlx
genes, such as Dlx-5 and Dlx-6, which are
expressed in ectomesenchyme in the mandibular
primordium.
50. Further functional support for the code model comes
from misexpression of Barx-1 in distal
ectomesenchyme cells, which results in incisor tooth
germs developing as molars.
Barx-1 expression is localized to proximal
ectomesenchyme (molar) by a combination of
positive and negative signals from the oral ectoderm
51. FGF-8 localized in proximal ectoderm induces Barx-
1 expression, whereas BMP-4 in the distal ectoderm
represses Barx-1 expression.
Expression of Barx-1 experimentally induced in distal
(presumptive incisor) ectomesenchyme by inhibition
of BMP signaling has the effect of repressing Msx
gene expression, which is induced in distal
ectomesenchyme by BMP-4.
52. The transformation of incisors into molars thus may
require a combination of loss of “incisor” genes (Msx)
and gain of “molar” genes (Barx-1).
It has also been reported that the transcriptional
regulator Isl1, a LIM homeodomain–containing
protein, plays a role in tooth formation and
patterning.
53. On the other hand, the clone model proposes that
each tooth class is derived from a clone of
ectomesenchymal cells programmed by epithelium
to produce teeth of a given pattern .
54. Instructive Signals for Patterning
Recombinations of incisor and molar epithelium with
mesenchyme from young mouse embryos (~ E10)
showed that when molar epithelium was recombined
with incisor mesenchyme, a molar tooth formed, and
when incisor epithelium was recombined with molar
mesenchyme, an incisor formed.
55. This led to the conclusion that the epithelium was
responsible for determining the type and shape of a
tooth.
Other recombinations with older embryos (~ E14),
however, produced different results, in which molar
epithelium recombined with incisor mesenchyme
resulted in incisor teeth and incisor epithelium
recombined with molar mesenchyme resulted in
molar teeth
56. Regionalization of Oral and Dental
Ectoderm
This shows that the Wnt-7B gene represses Shh
expression in oral ectoderm and thus the boundaries
between oral and dental ectoderm are maintained by
an interaction between Wnt and Shh signaling
similar to ectodermal boundary maintenance in
segmentation in insects.
57. Bud Stage
The bud stage is represented by the first epithelial
incursion into the ectomesenchyme of the jaw
The epithelial cells show little if any change in shape
or function.
The supporting ectomesenchymal cells are packed
closely beneath and around the epithelial bud.
As the epithelial bud continues to proliferate into the
ectomesenchyme, cellular density increases
immediately adjacent to the epithelial outgrowth. This
process is classically referred to as a condensation
of the ectomesenchyme.
58.
59. Bud-to-Cap Transition
Molecularly, Msx-1 is expressed with Bmp-4 in the
mesenchymal cells that condense around tooth buds.
Msx-1−/− embryos have tooth development arrested at
the bud stage, and Bmp-4 expression is lost from the
mesenchyme, suggesting that Msx-1 is required for Bmp-
4 expression.
Bmp-4 is able to maintain Msx-1 expression in wild-type
tooth bud mesenchyme, indicating that Bmp-4 induces
its own expression via Msx-1.
Tooth development can be rescued in Msx-1−/− embryos
by addition of exogenous BMP-4.
60.
61. Bmp-4 expressed in the bud mesenchyme is
required to maintain Bmp- 2 and Shh expression in
the epithelium.
Loss of Bmp-4 expression in Msx-1 mutants is
accompanied by loss of Shh expression at E12.5,
which can be restored by exogenous BMP-4.
Blocking SHH function with neutralizing antibodies
also results in loss of Bmp-2 expression, suggesting
Shh and Bmp-2 may be in the same pathway and
that down- regulation of Bmp-2 in Msx-1 mutants
may be downstream of the loss of SHH.
62. Blocking SHH signaling using neutralizing
antibodies or forskolin shows that at E11 to E12,
SHH is required for dental epithelium proliferation to
form tooth buds, whereas blocking at E13 affects
tooth bud morphology, but these buds still can form
teeth.
63. Another homeobox gene with a role in the bud-to-
cap transition is Pax- 9.
Pax-9 is expressed in bud stage mesenchyme and
earlier in domains similar to Activin-βA and Msx-1 in
patches of mesenchyme that mark the sites of tooth
formation.
Pax-9−/− mutant embryos have all teeth arrested at
the bud stage. Despite being coexpressed, early
Activin-βA expression
64. Is not affected in Pax-9−/− embryos, and Pax-9
expression is not affected in Activin-βA−/− embryos.
These two genes are essential for tooth
development to progress beyond the bud stage and
thus appear to function independently; however,
changes occur in expression of other genes, such as
Bmp-4, Msx-1, and Lef-1 in Pax-9−/− tooth bud
mesenchyme
65. Signaling centres
There are three sets of transient signaling centers in
the dental epithelium that produce more than a
dozen different signaling molecules belonging to the
BMP, FGF, Shh, and Wnt families.
First come the initiation knots, which appear in the
dental placode and initiate budding of the tooth
epithelium.
66. Then appear the primary and secondary enamel
knots that initiate the bud-to-cap stage transition
and tooth crown formation.
Precursor cells of these knots are first detected at
the tip of the tooth buds by expression of the p21
gene, followed shortly after by Shh.
The primary enamel knots become visible
histologically as clusters of nondividing epithelial
cells in sections of molar cap-stage tooth germs .
67.
68. These clusters express genes for several signaling
molecules, including Bmp-2, Bmp-4, Bmp-7, Fgf-4, Fgf-9,
Wnt-10b, Slit-1, and Shh .
Three-dimensional reconstructions of the expression of
these genes have revealed highly dynamic spatial and
temporal nested patterns in the enamel knot.
On the whole, receptors for the enamel knot signals are
localized in the epithelial cells surrounding the enamel
knot. Each cap- stage molar tooth germ has a single
primary enamel knot that induces formation of secondary
enamel knots at the tips of the future cusps and thereby
regulate crown patterning.
69. Fgf-4 and Slit-1 may be the best molecular markers
for enamel knot formation, because they have been
observed in both primary and secondary knots.
70. In summary, the enamel knot represents an
organizational center that orchestrates cuspal
morphogenesis.
The enamel knot shares many similarities with the
apical ectodermal ridge of developing limbs: both
consist of nondividing cells; both express Fgfs,
Bmps, and Msx-2; and both act as signaling
centers
71. Applied aspects
Among the first genes in which mutations were
shown to cause tooth agenesis in mice and humans
were MSX1 and PAX9.
These genes encode transcription factors, which
have essential functions in the mediation of BMP,
Wnt, and FGF signaling in early dental
mesenchyme.
Tooth development is arrested at the bud stage in
Msx1 and Pax9 knockout mice, and in humans
heterozygous loss of function mutations in MSX1
and PAX9 genes cause oligodontia (defined as more
than six missing teeth excluding wisdom teeth).
72. In addition to MSX1 and PAX9, the genes that have
been associated with nonsyndromic human
hypodontia (i.e., no defects in other organs) include
WNT10A, AXIN2, LRP6, GREM2, SPRY2, SPRY4,
and EDA.
Notably all these genes encode signals or inhibitors
of signaling
73. Human tooth agenesis is commonly associated with
congenital defects in other organs, most often with
ectodermal organs developing from the outer surface of
the embryo.
Conditions that affect two or more ectodermal organs are
called ectodermal dysplasia.
The most common of these is X-linked hypohidrotic
ectodermal dysplasia (HED), caused by mutations in the
EDA gene and characterized by oligodontia,hair loss, dry
mouth, and inability to sweat. Identical phenotypes result
from mutations in other components of the Eda signal
pathway, including the receptor EDAR and signal
mediator EDARADD
74. The stimulation of Eda expression in transgenic mice
induced the formation of extra teeth as well as
mammary glands and stimulated the growth of hair,
nails, and salivary glands. The EDA pathway is
unique because it seems to be necessary, almost
exclusively, for the formation of teeth and other
ectodermal organs, unlike the other conserved signal
pathways, which have more widespread functions.
75. Interestingly, WNT10A has come up as the most
common gene associated with human tooth
agenesis, and mutations in WNT10A have been
shown to account for more than half of the
nonsyndromic hypodontia cases.
Based on mouse experiments, the Wnt pathway
appears to be the most upstream signal pathway
and the inducer of tooth initiation. The inhibition of
Wnt signaling by overexpressing the Wnt inhibitor
Dkk1 in transgenic mice prevents the formation of
tooth placodes, and the initiation of teeth fails.
76. Conversely, when the Wnt pathway was
overactivated in the oral epithelium of transgenic
mouse embryos (β-catex3K14/+), dozens of teeth
were generated in succession.
This may indicate that the capacity for continuous
tooth formation, which was lost in the mouse (and
humans) during evolution, could be unlocked by
increased Wnt signal activity in the oral
epithelium.
77. There is already one potential treatment for the
prevention and cure of X-linked HED, the ectodermal
dysplasia syndrome caused by mutations in the EDA
gene
Clinical trials are currently ongoing to test whether
neonatal injections of EDA protein can prevent
hypodontia and other congenital defects of human X-
linked HED.