Hedgehog signaling regulates neurogenesis in the larval and adult zebrafish hypothalamus

Neurogenesis is now known to play a role in adult hypothalamic function, yet the cell-cell mechanisms regulating this neurogenesis remain poorly understood. Here we show that Hedgehog/Gli signaling positively regulates hypothalamic neurogenesis in both larval and adult zebrafish and is necessary and sufficient for normal hypothalamic proliferation rates. Hedgehog-responsive radial glia represent a relatively highly proliferative precursor population that gives rise to dopaminergic, serotonergic, and GABAergic neurons. in situ and transgenic reporter analyses revealed substantial heterogeneity in cell-cell signaling within the hypothalamic niche, with slow cycling Nestin-expressing cells residing among distinct and overlapping populations of Sonic Hh (Shh)-expressing, Hh-responsive, Notch-responsive, and Wnt-responsive radial glia. This work shows for the first time that Hh/Gli-signaling is a key component of the complex cell-cell signaling environment that regulates hypothalamic neurogenesis throughout life.Significance statement The extent, control, and consequences of adult neurogenesis in the hypothalamus are not well understood, despite the critical integrative role this conserved brain region plays in regulating basic metabolic and reproductive functions across vertebrate species. Here we show that proliferation in the zebrafish hypothalamus continues into adulthood and begin to define the complex signaling environment of the hypothalamic niche that may regulate this adult neurogenesis. Using new conditional gene regulation tools we show that the evolutionarily conserved Hedgehog/Gli signaling pathway positively regulates hypothalamic neurogenesis during postembryonic development and into adulthood. These studies suggest a mechanism for the control of hypothalamic growth and tissue renewal, as well as the plasticity in neuroendocrine cell populations that is now linked to hypothalamic function.