University:
American Career College
Course:
NURS115 | Intermediate Medical
Academic year:

2020
Views:

66

Pages:

40
Author:

Gracie Bullock

Developmental Genetics Prenatal Life • Zygote is formed after the spermatozoon nucleus enters the oocyte • The zygote starts to divide to 2 and then 4, 8, 16,…. to reach final 10,000 trillion cells • At the 12th week of gestation the fetus is recognizsably human • Normal development depends on: – Optimum maternal environment – Genetic integrity Prenatal Life (cont.) • Pre-embryonic (1w-4w) – Bilaminar – Trilaminar • Embryonic (4w-8w) – Organogenesis – Establishment of axes: • Craniocaudal, dorsoventral, proximodistal • Fetal (after 8w) – Rapid growth Fertilization & Gastrulation • Fertilization occurs in fallopian tube • From 200 million spermatozoon only one penetrates the oocyte • Morula: 16 cells at the third day • Blastocyst: – Inner cell mass or embryoblast – Outer cell mass or trophoblast • Gastrulation: conversion of inner cell mass to trilaminar disc (first of 2nd to the end of 3rd): – Ectoderm, mesoderm, endoderm Developmental Gene Families • Genetic studies on model organisms like fruit fly, mouse, zebra fish,… have identified genes of development • Developmental genes exert their functions mostly by transcription factors, which are under control of regulatory elements • Regulatory elements cause the genes to switch on and off during development Developmental Gene Families • Regulatory elements control the expression of genes • Split-hand-foot malformation (SHFM) is due to the deletion of enhancer of DLX5 gene Developmental Gene Family • Signaling molecules are similar across species: – TGF beta – Wnt family – Hedgehog family • Fundamental embryological processes: – – – – – Induction Segmentation Migration Differentiation apoptosis Somatogenesis & Axial Skeleton • Vertebrate axis formation is related to somitogenesis • Wnt and FGF play vital roles in specification of PSM • Notch, Wnt and FGF signalling pathways are essential components of segmentation of paraxial mesoderm Somatogenesis Somatogenesis • Notch signaling an is an important part of rostro caudal polarity • Ligands of Notch signaling: – delta-like-3 – mesoderm-posterior-2 • Mutations in the genes lead to : – AR spondylocostal dysostosis Spondylo-costal Dysostosis Allagile Syndrome • JAGGED1 Sonic Hedgehog-Patched GLI Pathway • Sonic hedgehog (SHH) gene induces cell proliferation in a tissue specific distribution • Sonic hedgehog is expressed in: – Notochord – Brain – Zone of polarizing activity of developing limb Sonic Hedgehog-Patched GLI Pathway Gorlin Syndrome Holoprosencephaly Homeobaox (HOX) Genes • Homeotic genes determine segment identity in drosophila • If expressed incorrectly leads to major abnormalities – Transformation of fly antennae to leg! • The genes are involved in: – Spatial pattern control – development HOX Genes Synpolydactyly Paired Box Genes • Paired box genes or PAX genes are highly conserved DNA sequences • Nine different PAX genes in human • Loss of function mutation in 5 of PAX genes are associated with developmental disorders in human PAX Genes • Mutations of the following PAX genes and their malformations: – PAX2: renal-coloboma syndrome – PAX3: Waardenburge syndroem1 – PAX6: aniridia Waardenburge Syndrome Aniridia HMG Box (SOX) Genes • HMG or High Mobility Group box (domain) is part of SOX genes • The SOX genes show homology with SRY gene • SOX genes are transcription regulators with important roles in embryological development • Campomelic dysplasia is because of mutation in SOX9 Campomelic Dysplasia Zinc Finger Genes • Proteins with zinc finger motif act as transcription factors • Any mutations in proteins with zinc finger motif are candidate of developmental disorders • Examples: – Greig cephalopolysyndactyly – Pallister Hall syndrome Greig Cephalopolysyndactyly Syndrome Greig Cephalopolysyndactyly Syndrome • GLI3 deletion • Abnormality in: – Head – Hand – foot Pallister Hall Syndrome Pallister Hall Syndrome • GLI3 frameshift mutation • Key features: – Polydactyly – Hypothalamic hamartoma – Imperforate anus Signal Transduction Genes • Signal transduction is the regulation of: – Cell division – Differentiation • Done by extracellular growth factors • Mutations in many genes are related to cancer • Some of mutations lead to developmental disorders Signalling Genes • Examples: – RET proto-oncogene – FGF receptors: • Craniosynostosis syndromes (Apert syndrome) • Skeletal dysplasia (achondroplasia) Apert Syndrome Achondroplasia Pharyngeal Arches • Pharyngeal or branchial arches appear in 4th and 5th weeks of development • Pharyngeal arches are separated by pharyngeal cleft and pharyngeal pouch • Organs and tissues originating from them: – Jaws and mastication muscles – Middle ear apparatus – Aorta and pulmonary arterial system – Thyroid, parathyroid, thymus,… Branchial System Pharyngeal Arches • Two important malformation associated with pharyngeal arches: – Branchio-oculo-facial syndrome (1st & 2nd arches) – DiGeorge syndrome (3rd & 4th arches) Branchio-oculo-facial Syndrome Cilia & Developmental Abnormalities • Mechanical functions: – Clearing respiratory system, moving sperms,.. – Circular motion in embryo to establish left-right asymmetry • Molecular antennae in embryo: – Optimal signaling of Wnt and hedgehog genes • Defects in cilial proteins: – ciliopathies Short-rib polydactyly Syndrome