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GENETICS CHP 10 (193-198) Developmental Genetics I. Intro/Basic Concepts 2-3% of all liveborn children have a birth defect (100,000/yr) leading cause of infant death in US Nonhuman model organisms used to study development due to conservation of genes and pathways across species o Ex: eyeless in Drosphilia homologous to Pax6 in mice and PAX6 in humans for eye development Conventional to capitalize all letters of names of human genes, only first letter of names of mouse genes, all lower-case letters for recessive mutations 3 major processes in development of embryo o axis specification- ventral/dorsal, ant/post, med/lat, L/R specification of polarity o pattern formation- through induction (cells signaling nearby cells) o organogenesis II. Paracrine signaling molecules Paracrine signaling- when interactions between cells are mediated by specific proteins that can diffuse across small distances to induce a response (into space surrounding cells) 4 major families of paracrine signaling molecules o FGF, Hedgehog, Wingless, and TGF-B A mutation in genes encoding these signals creates abnormal communication btw cells FGF (Fibroblast Growth Factor) o FGFRs (FGF receptors) consist of single peptide, 3 immunoglobulin-like domains, membrane spanning segment, and intracellular tyrosine kinase domain o FGF binds to FGFR phosphorylation activation of tyrosine kinase domain o FGFRs common in developing bone- autosomal dominant disorders of generalized bone growth o Achondroplasia- disproportionate short limbs Glycine arginine substitution in transmembrane domain of FGFR3 Restrains chondrocyte growth and proliferation (ie- too much inhibition) o Craniosynostosis- premature fusion of cranial sutures, also results in misshapen skulls and limb defects Can be caused by mutations in FGFR1, FGFR2, or FGFR3 Most common is Apert syndrome (mid face hypoplasia, fusion of digits, FGFR2 mutated) Hedgehog First isolated in Droshilia, most common vertebrae homolog is Sonic Hedgehog (Shh) o Axis specification, induction of motor neurons within neural plate, and patterning of limbs o Primary receptor is transmembrane receptor protein encoded by Patched o Patched inhibits fnc of another transmembrane receptor, Smoothened (encoded by Smo gene) o binding of Shh to Patched receptor causes disinhibition of smoothened and activation of signaling cascade to target GLI family of transcription factors o Gorlin syndrome- mutation in human PATCHED (PTC), causes rib anomalies, cysts of jaw, and basal cell carcinomas Wingless (WNT in humans) o dorsal/ventral axis (of limbs) and formation of brain, muscles, gonads, and kidneys o Code for glycoproteins that bind to frizzled and low-density lipoprotein (LDL) receptor related protein families o Homozygous WNT3 mutation causes tetra-amelia (absence of all 4 limbs) o Abnormal wnt signaling associated with formation of tumors TGF-B o Encode for proteins that form homodimers or heterodimers o Include TGF-B, BMP (bone morphogenic protein), activin, Vg1 families o Mutation in BMP family, cartilage derived morphogenetic protein 1 (CDMP1) causes skeletal abnormalities o RTK/MAPK signal transduction pathway regulated specific gene expression, division, differentiation, and death Used widely during development o Noonan syndrome- gain of function of PTPN11 gene, which encodes a protein that reacts with RTK/MAPK pathway; short stature, characteristic facial features, webbed neck, congenital heart disease o Disruptions of different components of same pathway cause different malformations but similar clinical features o Mutation in gene Noggin causes fusion of bones in joints (mutation of inhibitor of BMP function) o Genetics Chapter 10 pp. 199-205 I. Gene regulation Transcription factors: activate or repress sets of genes by regulating transcription of their DNA. Can lead to a cascade. Mutations in txn factors have pleiotropic (multiple phenotypes) effects. Members of a txn factor family usually share a common DNA-binding domain Examples of txn factor families include… o HOX, PAX, EMX, MSX (all homeobox families) o SOX family Includes SRY (sex-determining region of Y chromosome) gene SOX10 mutationHirschsprung disease (HSCR) HSCR: hypomotility of bowel Leads to constipation and distension of bowel HSCR can also be feature of OTHER birth defects like Trisomy 21 and Waardenburg syndrome o Thus, fits multifactorial model of inheritance: caused by combination of genes AND environmental factoras o T-box family Same txn factor often used in different developmental pathways Extracellular matrix proteins (secreted scaffolding molecules for tissues) also help mediate development o Fibrillin-1 and elastin coordinate microfibril assembly of ECM Mutation in fibrillin-1 Marfan syndrome Mutation in elastin supravalvular aortic stenosis Laminins help form attachments between cells and ECM II. Pattern Formation Body plan laid out during embryogenesis Shh txn factor involved in establishing midline Gastrulation Establishment of 3 germ layers: endoderm, mesoderm, ectoderm Major structural feature: primitive streak (thickened epiblast) Dominated by cell migration Neurulation + ectoderm Formation of neural tube Mediated by cellular induction (cells of one area influence cells of another area) controlled by Spemann-Mangold organizer Neural tissue induced from dorsal ectoderm under control of organizer Initiates organogenesis Divides ectoderm into neural tube, epidermis, and neural crest cells Mesoderm + endoderm Mesoderm=notochord, dorsal, intermediate, and lateral mesoderms, and head mesenchyme Notochord induces formation of neural tube Endoderm forms linings of GI tract and respiratory tree Endoderm-derived structures undergo much BRANCHING, controlled by FGFs and BMPs III. Axis Specification Anterior/Posterior Axis Defined by primitive streak (anteriorly has structure called a NODE) Patterning controlled by homeodomain (made up of homeobox genes) 3’ Hox genes expressed before 5’ Hox genes; Hoxa1 expressed anterior to Hoxa2 o both temporal and spatial colinearity Dorsal/Ventral Axis Noggin and Chordin (secreted from organizer) both dorsalize mesoderm BMP-4 ventralizes mesoderm Formation of Organs and Appendages Most of the genes that cause birth defects have prominent roles during this phase of development Genes affecting stages BEFORE organogenesis are possibly lethal Laterality Defects Situs solitus: normal organ arrangement Situs inversus: mirror image organ arrangement Situs ambiguus: randomization of organ arrangement Laterality defects more common in conjoined twins Cilia play a role in L/R axis o Dynein defectprimary ciliary dyskinesia o Most with PCD also exhibit situs inversus Genetics Ch10 pp. 206-210 A. Formation of organs and appendages a. Organogenesis occurs after gastrulation b. Ascertainment bias-harder to identify genes responsible for birth defects before this stage b/c often fatal B. Craniofacial development: Majority of craniofacial structures are derived from NC cells. Fate is specified by homebox genes. Some of these genes isolated by studying craniosynostosis syndromes. a. Fore/midbrain Neural crest -> nasal processes, palate, mesenchyme of first pharyngeal pouch b. Anterior hindbrain NC -> 2nd p. pouch, stapes, facial cartilage c. Cervical NC -> 3,4,6 pharyngeal arches (5th degenerates) d. Fate of NC determined by Hox i. Hoxa 3 inactivation in mice -> absent thymus, thyroid glands, vascular malformation e. Premature fusion of skull bones (craniosynostosis) assoc with other birth defects, often caused by FGFR mutations or MSX2 (NC apoptosis) i. Greig cephalopolysyndactyly-mutations in GLI3 (zinc finger tf) 1. C-terminal mutations-affecting both activator and repressor fcts ii. Pallister-Hall syndrome: mutations bet zinc finger and microtub anchor domains 1. Hypothalamic hamartomas, visceral anomalies, posterior polyd. iii. Isolated post. Polyd.: mutations of 3’ microtub anchor domain iv. Rubenstein-Taybi syndrome: loss of fct of Gli cofactor 1. Mental retardation, broad thumbs C. Box 10-1Animal Models in the Study of Human Development a. Mouse model construction i. Embryonic stem cells cultured to be knockout or transgenic ii. ESS implantd in blastocysts w/ recessive marker iii. Chimeras born from surrogate: some w/ genetic mods, some without b. Conditional knockout i. Condition knocked-out gene to occur only in certain cell type or specific tissue ii. Allows study of genes whose knockout would be lethal D. Development of the Limb: vertebrate limb composed of LP and somitic mesoderm. Growth and patterning controlled by AER, progress zone, ZPA. a. r-Fng and Wnt7a direct dorsal mesoderm i. En-1 (homeobox) blocks Wnt7a expression, directs ventralization b. Proximal/distal growth controlled by FGFs i. ZPA -> Shh directs ant/post limb bud axis c. Holt-Oram syndrome: caused by mutations in TBX5 (t-Box) i. Atrial septal defect is common; Nkx2-5 also cause the same defects d. Hox paralogs are partially redundant i. Ex. Synpolyd. And hand-foot-genital syndrome E. Organ Formation: reciprocal interactions bet epithelial cells and mesenchyme mediated by signaling molecules. a. IPF1 stimulates insulin in beta cells; IPF1 mutation prevents pancreatic development b. Dynamic interactions bet mesenchymal and epithelial cells continue to influence development i. Tooth development: Bmp-4 -> Msx1. Mutation in MSX1 disrupts tooth formation c. Osteoblast differentiation: regulated by Runx2 Disruption: mice w/o ossification. Heterozygotes: ossification abnormalities