Investigating molecular mechanisms and function of tanycyte-derived neurogenesis in the postnatal hypothalamus

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PROJECT SUMMARY In recent years, evidence now shows that tanycytes possess the ability to generate neurons in the postnatal hypothalamus. Tanycytes are radial glial cells that closely resemble neural progenitors in both morphology and gene expression profiles. While dietary and hormonal cues can regulate tanycyte-derived neurogenesis, the overall levels of tanycyte proliferation and tanycyte-derived neurogenesis are low and virtually undetectable in adult mice. The molecular mechanisms controlling neurogenic competence in tanycytes, and the precise physiological function of tanycyte-derived neurons remains poorly defined. Identifying molecular mechanisms that stimulate tanycyte-derived neurogenesis, to promote differentiation of tanycyte-derived neurons that modulate body weight and metabolism, is a new potential therapeutic for treating obesity and metabolic disorders such as type II diabetes. Recently, studies from the Blackshaw lab have identified the Nuclear Factor One (Nfi) family transcription factors (TFs), Nfia/b/x, as playing a critical role in regulating neurogenic competence in hypothalamic tanycytes. Under normal dietary conditions in male mice, Nfia/b/x-deficient tanycytes show enhanced proliferation and neurogenesis. Single-cell RNA-sequencing analysis of Nfia/b/x-deficient tanycytes and tanycyte-derived cells indicates that a substantial fraction of all tanycyte-derived neurons are GABAergic subtypes. A subset of these GABAergic neurons expresses the Leptin receptor (Lepr) and responds to leptin. The Blackshaw lab has also shown that tanycyte-derived neurons survive, integrate into hypothalamic circuits, and fire spontaneous action potentials. By analyzing genes differentially expressed between control and Nfia/b/x-deficient tanycytes, we have shown that Shh and Wnt signaling is upregulated in tanycytes following loss of Nfia/b/x. We also observed the downregulation of the Notch pathway in Nfia/b/x-deficient tanycytes. During development, Shh and Wnt pathways promotes neurogenesis in the hypothalamus. While Notch signaling pathway promote quiescence in retinal Müller glia and cortical astrocytes. Given these findings, I hypothesize that neurogenic competence in tanycytes is actively suppressed in the postnatal hypothalamus after neurogenesis and, hypothesize that tanycyte-derived neurons regulate body weight homeostasis and metabolism. To address these hypotheses, I propose the following two Aims: AIM 1: To investigate extrinsic regulators that positively or negatively control tanycyte-derived neurogenesis in the juvenile and young adult hypothalamus. This work will identify molecular mechanisms and gene regulatory networks that positively or negatively regulate tanycyte-derived neurogenesis in the postnatal hypothalamus. AIM 2: To determine the role of tanycyte-derived neurons on bodyweight homeostasis and metabolism. These studies will provide key insights into the physiological function of tanycyte-derived neurons in controlling body weight homeostasis and metabolism.