Genes and development Flashcards
What is a morphogen?
It is a signaling molecule that forms time-dependent concentration gradients to direct which cell type will be generated where.
Name 4 examples of morphogens
1) Retinoic Acid (RA)
2) Bone Morphogenetic Proteins (BMPs)
3) Sonic Hedgehog (SHH)
4) WNT protein families (WNTs)
What does BMP4 do?
Where does it bind?
It promotes epidermal tissue gene expression while inhibiting genes that trigger neuronal differentiation.
It is synthesized by ectodermal cells and secreted to extracellular space, where it binds to its receptor on ectodermal cells.
What 3 morphogens inhibit BMP4?
What does this do?
Noggin, Chordin, and Follistatin.
This leads to a lack of BMP4 action which allows activation of genes that trigger neuronal differentiation.
How is transcription factor SMAD activated?
When TGFß binds to its receptor (TGFß’s receptor not SMAD receptor), the engaged receptor phosphorylates and activates the transcription factor SMAD.
Describe the relationship b/w Retinoic Acid (RA) and Homeobox (HOX) genes.
HOX genes code for a large family of transcription factors that are critical for morophogenesis of the embryo. Increasing concentrations of RA activate gene expression of different HOX genes.
RA binds to RAr, the transcription factor receptor, which w/o RA bound is inhibited by an inhibitor protein. W/ RA bound, the inhibitor protein disengages and RAr binds to the RA response element (AKA RARE) to inc. transcription of HOX genes. This is important for structures and limb development.
How is RA related to the anterior and posterior axis?
A gradient of RA for anterior and posterior axis formation is critical. The axis is critical for limb formation.
There is an increasing concentration gradient of RA from the anterior TO the posterior axis. Different concentrations of RA activate different HOXd family members.
How do the opposing gradients of BMP and SHH control the fate of neuroblasts in the developing neural tube?
Neuroblasts exposed to hight SHH and low BMP will differentitate into motor neurons.
Neuroblasts exposed to low SHH and high BMP will differentiate into sensory neurons
How does the notch/delta signaling pathway work?
In progenitor cells, activation of Notch signaling leads to cleaveage of the Notch intracellular domain (NICD). NICD translocates to the nucleus, binds to a transcriptional complex, and activates target genes that inhibit differentiation.
NOTE: In differentiating cells, notch signaling is not active.
What happens when a growth factor binds to a specific Receptor Tyrosine Kinase (RTK)
It leads to dimerization of adjacent monomers of RTKs. After dimerization transphosphorylation occurs, activating downstream signaling cascades.
Thus in the absence of a ligand RTKs are monomers.
What is a teratogen?
It is an environmental agent that disrupts normal development.
When is the risk of congenital anomalies highest?
during wks 3-8 (the formation of organs period)
Name a common tetratogen and the defects that may occur from it?
Alcohol.
Growth and mental deficiencies, and even microcephaly, joint defects, and congenital heart disease.
Why are cholesterol lowering agents considered a tetratogen?
SHH requires binding to cholesterol to be active. Cholesterol synthesis inhibitors can impair normal SHH signaling and can cause abnormal development.
Can a deficiency or excess of RA lead to dysmorphogenesis?
Both can lead to development problems.
Why is accutane (an acne medication) a tetratogen?
It has lots of RA in it and exposure to high RA can lead to absent or defective EARS, absent or small JAWS, cleft palate, and abnormalities of the CNS.
What axes do RA and SHH relate to?
RA: Rostral-caudal axis
SHH: Dorsal-ventral axis
What does the tetratogen thalidomide do?
It can inhibit angiogenesis in embryos.
It is usually prescribed as a mild sedative to pregnant women, and it can also be used to reduce tumor growth.
