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. In this study, we show that tanycyte-specific disruption of the NFI family of transcription factors (Nfia/b/x) robustly stimulates tanycyte proliferation and tanycyte-derived neurogenesis. Single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) analysis reveals that NFI (nuclear factor I) factors repress Sonic hedgehog (Shh) and Wnt signaling in tanycytes and modulation of these pathways blocks proliferation and tanycyte-derived neurogenesis in Nfia/b/x-deficient mice. Nfia/b/x-deficient tanycytes give rise to multiple mediobasal hypothalamic neuronal subtypes that can mature, fire action potentials, receive synaptic inputs, and selectively respond to changes in internal states. These findings identify molecular mechanisms that control tanycyte-derived neurogenesis, which can potentially be targeted to selectively remodel the hypothalamic neural circuitry that controls homeostatic physiological processes.

Ptbp1 deletion does not induce glia-to-neuron conversion in adult mouse retina and brain

“…The acute brain slices were generated as previously described (K. Liu et al 2017;Yoo et al 2021). Ptbp1-Het or Ptbp1-KO (P54 to P73, male) were anesthetized with isoflurane and decapitated, and the brains were rapidly removed and chilled in ice-cold sucrose solution containing 76 mM NaCl, 25 mM NaHCO3, 25 mM glucose, 75 mM sucrose, 2.5 mM KCl, 1.25 mM NaH2PO4, 0.5 mM CaCl2, and 7 mM MgSO4 (pH 7.3).…”

Irx3 and Irx5 - Novel Regulatory Factors of Postnatal Hypothalamic Neurogenesis

“…In combination with BrdU labeling, these lineage tracing experiments highlight the proliferative ability of ventricular zone in the postnatal mouse hypothalamus. By using Rax-CreER (targeting all tanycytes), tanycytes were shown to give rise to both neurons and glia in the postnatal and juvenile mouse hypothalamus ( Pak et al, 2014 ; Yoo et al, 2021 ). These findings were further supported by scRNA-seq analysis of Rax-CreER lineage cells ( Yoo et al, 2021 ).…”

“…By using Rax-CreER (targeting all tanycytes), tanycytes were shown to give rise to both neurons and glia in the postnatal and juvenile mouse hypothalamus ( Pak et al, 2014 ; Yoo et al, 2021 ). These findings were further supported by scRNA-seq analysis of Rax-CreER lineage cells ( Yoo et al, 2021 ). However, it is worth noting that the neurogenic and gliogenic abilities of Rax + tanycytes appear to be drastically reduced at adult stage, as tanycytes labeled by Rax-CreER at P60 generate very few neurons under physiological conditions ( Pak et al, 2014 ).…”

“…In addition, these RGL-NSCs are molecularly distinct from tanycytes of the mouse hypothalamus, as they do not express the canonical markers, such as Rax and Crym ( Figure 4A ). Indeed, comparison with Rax-CreERT marked cells ( Yoo et al, 2021 ) at similar postnatal timepoints using a ‘reference-based integration’ analysis with the single-cell R toolkit Seurat ( Stuart et al, 2019 ) reveals minimal overlap between the progeny of Rax-CreERT labeled tanycytes and those of RGL-NSCs ( Figure 4B ). By pseudo-temporal analysis ( Wolf et al, 2019 ), RGL-NSCs are inferred to possess the potential of differentiating into both tanycyte and OPC lineages ( Figure 4C ).…”

“…In addition to extrinsic factors, genetic studies have begun to unveil the role of intrinsic factors in the control of postnatal ARC neurogenesis. For example, deletion of the nuclear factor I family of transcription factors ( Nfia / b / x ) in Rax + tanycytes results in activation of Shh and Wnt signaling, which in turn stimulates proliferation of tanycytes and their robust neurogenic differentiation in postnatal mouse hypothalamus ( Yoo et al, 2021 ). This study highlights the inhibitory functions of Nfia / b / x TFs in restricting the neurogenic differentiation of tanycytes and suggests the involvement of Shh and Wnt signaling in the control of hypothalamic postnatal neurogenesis.…”