Developmental Genetics Dr. E. M. Honey Department Genetics University of Pretoria

Main events in the development of a human infant Pre-embryonic First cell division 30 hours Zygote reaches uterine cavity 4 days Implantation 5-6 days Formation of bilaminar disc 12 days Lyonization in female 16 days Formation of trilaminar disc 19 days Closure of the neural tube 24 days

Main events in the development of a human infant Embryonic stage Organogenesis 4-8 weeks Brain and spinal cord are forming 4 weeks First sign of heart and limb buds Brain, eyes, heart and limbs developing 6 weeks Bowel and lungs begin to develop Digits have appeared Ears, kidneys and muscle are developing 8 weeks Palate closes and joints form 10 weeks Sexual development almost complete 12 weeks

Main events in the development of a human infant Fetal stage Fetal movements felt weeks Eyelids open Fetus now viable with special care weeks Rapid weight gain due to growth and Accumulation of fat as lungs mature weeks

Tissue origins Ectoderm Central nervous system Peripheral nervous system Epidermis including hair and nails Subcutaneous glands Dental enamel Mesoderm Connective tissue Cartilage and bone Smooth and striated muscle Cardiovascular system Urogenital system Endoderm Thymus and thyroid Gastro-intestinal system Liver and pancreas

Genes involved in the developmental process Gene and gene families identified in the fruit fly Drosophila melanogaster Produces transcription factors - controls RNA transcription from the DNA template by binding to specific regulatory DNA sequences - switch genes on and off by activating or repressing gene expression - regulating fundamental embryological processes

Genes involved in the developmental process Mutations in various members of these gene families can result in either isolated malformations or multiple congenital anomaly syndromes Examples: Segmentation genes, Homeobox genes, Paired- box(PAX) genes, SRY-type HMG box(SOX) genes, T- box(TBX) genes, Zinc finger genes, signal transduction(“signalling”) genes.

Genes involved in the developmental process Segmentation genes: Sonic Hedgehog, Desert Hedgehog and Indian Hedgehog - left-right asymmetry, polarity in the CNS, organogenesis and formation of the skeleton Homeobox genes: 39 identified, embryo can’t survive Homeobox-like domain: MSX2(craniosynostosis) and EMX2(schizencephaly) Paired-box(PAX) genes: 9 identified - PAX3 – Waardenburg syndrome - PAX2 – renal-coloboma syndrome - PAX6 – aniridia(WAGR syndrome)

Genes involved in the developmental process SRY-type HMG Box(SOX) genes – role in male sexual determination - SOX9 on Chr 17 causes camptomelic dysplasia - SOX10 on Chr 22 causes Waardenburg syndrome associated with Hirschprung didease T-BOX(TBX) genes - role in mesoderm formation and notochord differentiation - TBX3 causes ulnar-mammary syndrome - TBX5 causes Holt Oram syndrome

Genes involved in the developmental process Zinc finger genes – complex of 4 amino acids which form a complex with a sinc iron - GLI3 on chr 7 – deletions causes Greig cephalopolysyndactily, frameshift mutations causes Pallister-Hall syndrome Signalling genes – implicated in cancer - RET proto-oncogene causes Hirschprung disease - Fibroblast growth factor receptors

Fibroblast growth factor receptors Craniosynostosis syndromes FGFR1 8p11 Pfeiffer FGFR2 10q25 Apert Crouzon Jackson-Weiss Pfeiffer FGFR3 4p16 Crouzon Skeletal dysplasia FGFR3 4p16 Achondroplasia Hypochondroplasia Thanatophoric dysplasia

Limb as a developmental model 4 main phases: 1. Initiation – FGF 2, 4 or 8 2. Specification - HOX genes limb type 3. Tissue differentiation – SHH, HOXA, HOXD 4. Growth – FGF genes important

Sexual differentiation X and Y chromosomes SRY gene – transcription regulator Mutations XY females Crossover XX males Other genes plays a role e.a. SOX9