Transcript Developmental Genetics

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
Zygote reaches uterine cavity
Implantation
Formation of bilaminar disc
Lyonization in female
Formation of trilaminar disc
Closure of the neural tube
30 hours
4 days
5-6 days
12 days
16 days
19 days
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
Eyelids open
Fetus now viable with special care
Rapid weight gain due to growth and
Accumulation of fat as lungs mature
16-18 weeks
24-26 weeks
28-38 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, Pairedbox(PAX) genes, SRY-type HMG box(SOX) genes, Tbox(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
FGFR2
10q25
FGFR3
Skeletal dysplasia
FGFR3
4p16
4p16
Pfeiffer
Apert
Crouzon
Jackson-Weiss
Pfeiffer
Crouzon
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