Distinct temporal requirements for Sonic hedgehog signaling in development of the tuberal hypothalamus

Abstract

ABSTRACT

Development of the basal hypothalamus through anisotropic growth

“…Once induced, Shh diffuses out of RDVM cells to establish a morphogen gradient in adjacent diencephalic cells that is translated into a cell‐intrinsic GliA‐GliR gradient, similar to that found in the spinal cord . The predicted GliA‐GliR gradient is considered to set up an early dorso‐ventral pattern, characterised by domains of Shh and the homeodomain TFs, Nkx2.1, Nkx2.2 and Pax6 (Figure B, inset): Nkx2.2 is expressed in a diagonal stripe of cells that span the accepted basal‐alar boundary .…”

“…The predicted GliA‐GliR gradient is considered to set up an early dorso‐ventral pattern, characterised by domains of Shh and the homeodomain TFs, Nkx2.1, Nkx2.2 and Pax6 (Figure B, inset): Nkx2.2 is expressed in a diagonal stripe of cells that span the accepted basal‐alar boundary . Recent work validates this idea: in mice where Shh is deleted in RDVM cells, (Shh Δhyp mice), Nkx2.2 is reduced and Pax6 expands ventrally . Cross‐repressive TF interactions may then sustain pattern: in zebrafish, triple knockdown of nkx2.1, nkx2.4a and nkx2.4b leads to the ventral expansion of pax6 …”

“…As noted, it remains to be seen whether a similar programme builds the hypothalamus in other species. Current lineage‐tracing studies in the mouse show that Shh ‐expressing progenitors (either posterior RDVM cells or Shh +ive neuroepithelial cells) give rise to tuberal and mammillary regions, although they do not provide evidence that anterior regions are generated from Shh ‐expressing progenitors. Instead, many existing models suggest that an alar progenitor domain lies between telencephalic and Shh ‐expressing basal hypothalamic progenitors .…”

“…In this way, the bHyp population quickly gives rise to molecularly‐distinct daughter populations: Fgf10 +ive cells that overlap with peripheral Shh +ive cells. The spatial resolution of Shh and Fgf10 expression is linked to proliferation and depends on the inter‐regulation of, and balance between, Shh and BMP signalling: in chick, if Shh/Shh signalling are aberrantly maintained, proliferation is not stimulated; similarly, mouse Shh Δhyp embryos show a rostral shift in BMP4 expression and an expanded zone of non‐proliferating Tbx3 ‐expressing RDVM cells …”

“…Potentially, this creates a temporal dimension, where waves of progenitors arise in a spatio‐temporal manner from anterior neuroepithelial Shh +ive progenitors, providing the opportunity to build complex arrays of basal hypothalamic neurones. In support of this idea, genetic or pharmacological studies that down‐regulate/prevent Shh or Rx activity leads to the failure of differentiation of many different neuronal subtypes of the basal‐anterior and tuberal hypothalamus, including pomc, avp, otp, TH and Sst neurones, and neurones of the tract of the post‐optic commissure . However, future lineage‐tracing studies that build on previous/recent studies are needed to tease out which neurones require Shh non‐autonomously vs autonomously; namely, to distinguish between neurones born from progenitors that respond to Shh (but do not express it) vs neurones that differentiate from Shh +ive progenitor populations.…”