Lecture 5 Flashcards
Which cells will ultimately become the hypothalamus
The cells that lie above the prechordal mesoderm
Which structure is responsible for inducing early hypothalamic progenitors
The prechordal mesoderm
Sonic hedgehog is necessary and sufficient for hypothalamic development T or F
F – it is necessary but not sufficient
Explain how hypothalamic cells are born from an FGF10 positive progenitor
The FGF10 positive progenitor divides. On of these daughters downregulates sonic hedgehog remains in place as an FGF10 positive proliferating progenitor. The other daughter is displaced laterally where it forms an anterior or mammillary progenitor that moves away anteriorly or posteriorly
What is the role of sonic hedgehog in directing the daughters of these FGF10 positive progenitors
Sonic hedgehog acts to select anterior progenitors produced by the division of FGF10 positive progenitors
What are the overall effects of ligand-dependant antagonism
It acts to steepen and restrict the gradient producing a smaller and more local effect that limits the number of cells that can form
What is the converse effect of LDA if a cell begins to stop expressing sonic hedgehog
If a cell stops expressing sonic hedgehog and its receptors then LDA is stopped. This now supports the spread of sonic hedgehog further into neighbouring territories widening the gradient and increasing the distance the sonic hedgehog ligands can travel.
What can be said about the transcriptional regulation of sonic hedgehog in the various regions of the body in which is it expressed
Sonic hedgehog expression is regulated by the activity of multiple transcription factors acting on gene enhancers/promoters. Transcription of the sonic hedgehog gene is regulated by different enhancer elements in the future hypothalamus compared to the future spinal cord/hindbrain and midbrain
What is the name of the enhancer that regulates sonic hedgehog expression in the hypothalamus
Sonic hedgehog brain enhancer 2 (SBE2)
Describe the structure of the enhancer that controls sonic hedgehog expression in the hypothalamus
It contains binding sites for tbx2 SOX2 and GliA
Describe how the various transcription factors regulate sonic hedgehog at the level of the enhancer controlling its expression in the hypothalamus
Sox2 binds to SBE2 to upregulate sonic hedgehog expression. Tbx2 repressed sonic hedgehog by displacing Sox2. Both GliA and Sox2 transcription factors are required to activate sonic hedgehog expression
What causes sonic hedgehog expression at the transcriptional level in the hypothalamus
Both GliA and Sox2 transcription factors are required to activate sonic hedgehog expression. Sox2 expression is induced by BMP antagonists such as chordin. Sonic hedgehog and nodal from the early prechordal mesoderm induce GliA and hence lead to sonic hedgehog transcription
Explain how sonic hedgehog transcription becomes downregulated in response to the late prechordal mesoderm
Upon formation of the pre-hypothalamic progenitor the prechordal mesoderm begins to upregulate BMP7. Tbx2 is induced in response to BMP7 signalling and leads to the subsequent downregulation of sonic hedgehog by displacing Sox2 from SBE2.
What is the effect of the subsequent downregulation of sonic hedgehog that is seen in the pre-hypothalamic progenitors in response to BMP7 secretion by the late prechordal mesoderm
By downregulating sonic hedgehog and its receptors the already secreted sonic hedgehog ligand can now diffuse further. This acts to cause a spread of sonic hedgehog into neighbouring cells that is in fact sufficient to induce a subsequent sonic hedgehog upregulation in those cells. Effectively now we see the expression of sonic hedgehog moving anteriorly whilst behind it is being switched off.
Outline what happens to the proliferating stem-like pre-hypothalamic progenitor leading up to the specification of anterior progenitors
The proliferating progenitor is co-expressing both Tbx2 and FGF10. This cell divides and then one daughter begins to downregulate sonic hedgehog and is retained as a proliferating progenitor. The second daughter is displaced anteriorly where it now sees a higher sonic hedgehog level and subsequently begins to upregulate sonic hedgehog itself through LDA. This acts to specify it as an anterior progenitor
