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

Abstract

Sonic hedgehog (Shh) plays well characterized roles in brain and spinal cord development, but its functions in the hypothalamus have been more difficult to elucidate owing to the complex neuroanatomy of this brain area. Here, we use fate mapping and conditional deletion models in mice to define requirements for dynamic Shh activity at distinct developmental stages in the tuberal hypothalamus, a brain region with important homeostatic functions. At early time points, Shh signaling regulates dorsoventral patterning, neurogenesis and the size of the ventral midline. Fate-mapping experiments demonstrate that Shh-expressing and-responsive progenitors contribute to distinct neuronal subtypes, accounting for some of the cellular heterogeneity in tuberal hypothalamic nuclei. Conditional deletion of the hedgehog transducer smoothened (Smo), after dorsoventral patterning has been established, reveals that Shh signaling is necessary to maintain proliferation and progenitor identity during peak periods of hypothalamic neurogenesis. We also find that mosaic disruption of Smo causes a non-cell autonomous gain in Shh signaling activity in neighboring wild-type cells, suggesting a mechanism for the pathogenesis of hypothalamic hamartomas, benign tumors that form during hypothalamic development.

Comparative effects of mercury chloride and methylmercury exposure on early neurodevelopment in zebrafish larvae

“…Shha controls key developmental processes, including neural tube patterns, neural stem cell proliferation, and survival of neurons and glial cells. 38,39 Ngn is a marker for neuronal precursors and expressed in the central nervous system regulated by Shha. 40 Ngn1 is expressed in the neural plate and can induce the expression of Nrd, which may in turn cause proliferative neural precursor cells to become post-mitotic neurons.…”

Development of the basal hypothalamus through anisotropic growth

“…25 Elegant analyses in mouse show that Shh expression in RDVM cells is regulated by a unique enhancer, SBE2 (Shh brain enhancer 2). 26 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, [27][28][29] similar to that found in the spinal cord. 30 The predicted GliA-GliR gradient is considered to set up…”

“…First, having initially acted as a morphogen to pattern the early hypothala- neurones of the tract of the post-optic commissure. 1,8,18,[27][28][29]36,44,45 However, future lineage-tracing studies that build on previous/recent studies 8,27,29,51 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.…”

“…Schematics show hypothalamus relative to underlying tissues: prechordal mesendoderm (A); or Rathke's pouch (C,D). ant, anterior; mam, mammillary; os, optic stalk; tub, tuberal expands ventrally 29. 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 32.…”

Analysis of stress responses inAstyanaxlarvae reveals heterogeneity among different populations

“…In cavefish, the expression of both nkx2.1a and lhx6 are significantly expanded as compared to surface fish, suggesting that these factors may be involved in the evolutionary modification of the telencephalon. Similarly, the hypothalamus is modulated by numerous molecular factors, but one that is particular important is sonic hedgehog (shh) (Corman et al, 2018). Expression of shh has been shown to be expanded both along the midline as well is in the hypothalamus (Menuet et al, 2007).…”