BMS2042 Lecture Notes - Lecture 22: Epiblast, Antennapedia, Sonic Hedgehog
30 May 2018
School
Department
Course
Professor
Week 8. Developmental genetics, Sex
determination & DSD
DEVLOPMENTAL GENETICS
• Development is a progressive change in cell and tissue organisation (cell structure and function)
• Development involves specialisation of cells and tissues and morphogenesis
• Cells in embryonic development are functionally equivalent hence removal of part of the embryo
can be compensated for
• Cell fate:
1. Specification: acquires specific characteristics but can still be influenced by
environmental cues
2. Determination: cell has irreversible committed to acquire final traits/attributes
3. Differentiation: stepwise acquisition of a stable cellular phenotype of gene expression.
Structural and biochemical features are established
• Combinatorial gene regulation:
2 governing principles
1. Differential gene expression
2. Differential diffusion of local signalling molecules
find more resources at oneclass.com
find more resources at oneclass.com
• Morphogens: diffusible molecules that influence cell fate in a concentration-dependent manner
(cell differentiation is based on morphogen gradients)
• Major paracrine signalling: Hedgehog, Wnt, FGF and TGF-B
• Master control genes
o Encode TF (transcription factors) that work with signalling molecules
Sonic hedgehog
• Roles in:
o Left-right asymmetry
o Polarity of CNS
o Somite limb development
o Chondrogenesis
o Testis development
• Diffusion of Hh protein creates a gradient -> different concentrations
(morhagen) induce different cell fates
• Signalling patterns the polarity of the neural tube by establishing the
ventral aspect
• Expressed in notochord and floor plate of neural tube
• Diffuses dorsally and concentration determines fate of neurons
(increased concentration = ventral intermediate = motor
decreased concentration = interneurons)
• Mutations can cause congenital defects and cancer
eg. holoprosencephaly
Hox genes
• Expressed in overlapping domains along anterior-posterior axis
• Encodes TF with a homeodomain, a conserved DNA-binding module
(homeodomain = helix-turn-helix that can bind major groove of DNA)
• Controls patterning along the body axis -> position information
• Order of hox genes along chromosome parallels:
o Position in embryo in which that gene is expressed
o Time in development when it is expressed
• Genes early in the series expressed more anteriorly and first
• Major expression sites: somites, brain and spinal cord, limbs
• Hox genes = ordered clusters of homeobox genes
• Mutations can case homeotic transformations = transformation of one
body part into another
eg. antennapedia specifies identity of thoracic leg segments
mutation -> expression in head -> legs instead of antenna
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find more resources at oneclass.com
• Induction and genes that encode signalling molecues:
o Induction: developmental process whereby signal released from one group of cells
influences the development of an adjacent group of cells
• Pleiotropy = single gene influences multiple phenotypic traits
-> single underlying genetic defect can result in abnormalities in more than one organ/structure
eg. branchio-oto-renal dysplasia
EYA1 gene -> eyes, ears and kidneys
• Organogenesis
o Genes encoding TF and signalling molecules interact to direct the development of
specific organs
o Exact functions vary depending on cell type and developmental context
• Limb is patterned over three axes
• Signalling centres:
Apical ectodermal ridge (AER)
o Required for limb outgrowth and proximal-distal
development
o Releases fibroblast growth factors (FGF-2 and 8)
-FGF keeps cells proliferating
FGF secreted -> gradient -> proliferation signals to
underlying cells -> in progress zone become distal
Less FGF = proximal specification
More FGF = distal specification
Thalidomide (morning sickness medication) ->
birth defects -> no cell growth -> most cells
exposed to high concentration of FGF -> all
become distal (truncated limbs)
Zone of polarising activity (ZPA)
o Region of mesoderm at posterior border of limb
o Establish anterior-posterior axis
o If ZPA is grafted to anterior region -> mirror image
o Morphogen = SHH
-> gradient establishes anterior-posterior patterning
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
Structural and biochemical features are established: combinatorial gene regulation: Induction: developmental process whereby signal released from one group of cells influences the development of an adjacent group of cells: pleiotropy = single gene influences multiple phenotypic traits. > single underlying genetic defect can result in abnormalities in more than one organ/structure eg. branchio-oto-renal dysplasia. Eya1 gene -> eyes, ears and kidneys: organogenesis, genes encoding tf and signalling molecules interact to direct the development of specific organs, exact functions vary depending on cell type and developmental context. Limb is patterned over three axes: signalling centres: Apical ectodermal ridge (aer: required for limb outgrowth and proximal-distal development, releases fibroblast growth factors (fgf-2 and 8) Fgf secreted -> gradient -> proliferation signals to underlying cells -> in progress zone become distal. Thalidomide (morning sickness medication) -> birth defects -> no cell growth -> most cells exposed to high concentration of fgf -> all become distal (truncated limbs)
