Control of neurogenic competence in mammalian hypothalamic tanycytes

Abstract

Hypothalamic tanycytes, radial glial cells that share many features with neuronal progenitors, can generate small numbers of neurons in the postnatal hypothalamus, but the identity of these neurons and the molecular mechanisms that control tanycyte-derived neurogenesis are unknown. We report that tanycyte-specific disruption of the NFI family of transcription factors (Nfia/b/x) stimulates proliferation and tanycyte-derived neurogenesis. Single-cell RNA- and ATAC-Seq analysis reveals that NFI factors repress Shh and Wnt signaling in tanycytes, and small molecule inhibition of these pathways blocks proliferation and tanycyte-derived neurogenesis in Nfia/b/x-deficient mice. We show that Nfia/b/x-deficient tanycytes give rise to multiple mediobasal hypothalamic neuronal subtypes that can mature, integrate into hypothalamic circuitry, and selectively respond to changes in internal states. These findings identify molecular mechanisms controlling tanycyte-derived neurogenesis that can potentially be targeted to selectively remodel hypothalamic neural circuitry controlling homeostatic physiological processes.

Adult-born proopiomelanocortin neurons derived from Rax-expressing precursors mitigate the metabolic effects of congenital hypothalamic proopiomelanocortin deficiency

“…Rax- negative frizzy cells expressing tdTomato were more broadly distributed, suggesting that frizzy cells move over long distances and downregulate Rax while migrating. Frizzy cells were also observed by other studies, such as by Yoo and colleagues [ 16 ] who used the same Rax-CreERT2 /+ line, and showed a reporter-positive cell with glial cell-like morphology that is identical to a frizzy cell. Another tanycyte lineage-tracing study using Fgf10-CreERT2 /+ mice described reporter-positive glial-like cells [ 40 ] that are morphologically identical to frizzy cells.…”

“…However, frizzy cells may represent a subtype of protoplasmic astrocytes with low GFAP expression/immunoreactivity [ 30 , 41 ], and potentially with neural progenitor characteristics akin to a subtype of hippocampal astrocytes [ 42 ]. In a recent RNA-Seq study that categorized cells of the Rax lineage, frizzy cells were probably classified as astrocytes and/or oligodendrocyte precursor cells, and it was noted that astrocytes appear to arise directly from α1 and α2 tanycytes [ 16 ]. Interestingly, we observed that dorsal α1 tanycytes translocated into the parenchyma with nearby RAX + frizzy cells ( Figure 2B2 inset), which may offer a snapshot into the process of tanycytes entering the parenchyma and differentiating into frizzy cells.…”

“…Our results showed that Pomc neurons born from Rax + progenitors develop rapidly and form long-range projections within a week, suggesting fast neuronal maturation, in agreement with findings that adult-born tanycyte-derived neurons become leptin-responsive within 8 days [ 14 ]. A recent study also demonstrated that tanycyte-derived neurons are capable of firing action potentials within 12 days, receive synaptic inputs, and thus integrate into the hypothalamic neurocircuitry [ 16 ]. Newly generated Pomc neurons successfully incorporated into functional neural circuits—as indicated by improved glucose tolerance in males, improved insulin sensitivity, and reduced fat mass that were observed in both sexes, but more pronounced in males.…”

“…Besides parenchymal progenitors, another population of adult hypothalamic stem/progenitor cells is tanycytes – radial glia-like ependymal cells lining the third ventricle – that can differentiate into glia and neurons [ [11] , [12] , [13] , [14] , [15] ]. While tanycytes were recently shown to give rise to some POMC neurons in the early postnatal period (postnatal day 8) [ 16 ], the capacity of tanycytes to generate functionally relevant POMC neurons during adulthood is unknown. The present study was designed to systematically test whether tanycytes can differentiate into melanocortin-secreting POMC neurons that integrate into the normal anatomical projection pathways, and rescue the obesity phenotype caused by the loss of Pomc expression in Arc Pomc- deficient mice.…”

Single-cell analysis of early chick hypothalamic development reveals that hypothalamic cells are induced from prethalamic-like progenitors

“…Congenital metabolic disorders and obesity can result from Mendelian mutations in transcription factors that control hypothalamic patterning (Blanchet et al, 2017;Holder et al, 2000), and mutations in genes identified as important for controlling hypothalamic and neurogenesis in this study may contribute to multigenic disorders that may have a hypothalamic origin, such as Type 2 diabetes, sleep disorders, and depression (Bao et al, 2008;Biran et al, 2015;Dearden and Ozanne, 2015). Understanding the molecular mechanisms controlling early hypothalamic development is also critical to efforts towards induced differentiation of specific hypothalamic neuronal subtypes from embryonic stem (ES) or induced pluripotent stem (iPS) cells (Merkle et al, 2015;Nagasaki et al, 2015;Seifinejad et al, 2019;Wang et al, 2016), as well as for directed reprogramming of hypothalamic glial cells (Kano et al, 2019;Yoo et al, 2021). Cell-based approaches such as these may ultimately hold the potential for the directed rewiring of core hypothalamic regulatory circuitry for treating a broad range of homeostatic disorders.…”