Hypothalamic radial glia function as self-renewing neural progenitors in the absence of Wnt/ß-catenin signaling

Abstract

The vertebrate hypothalamus contains persistent radial glia that have been proposed to function as neural progenitors. In zebrafish, a high level of postembryonic hypothalamic neurogenesis has been observed, but the role of radial glia in generating these new neurons is unclear. We have used inducible Cre-mediated lineage labeling to show that a population of hypothalamic radial glia undergoes selfrenewal and generates multiple neuronal subtypes at larval stages. Whereas Wnt/β-catenin signaling has been demonstrated to promote the expansion of other stem and progenitor cell populations, we find that Wnt/β-catenin pathway activity inhibits this process in hypothalamic radial glia and is not required for their self-renewal. By contrast, Wnt/β-catenin signaling is required for the differentiation of a specific subset of radial glial neuronal progeny residing along the ventricular surface. We also show that partial genetic ablation of hypothalamic radial glia or their progeny causes a net increase in their proliferation, which is also independent of Wnt/β-catenin signaling. Hypothalamic radial glia in the zebrafish larva thus exhibit several key characteristics of a neural stem cell population, and our data support the idea that Wnt pathway function may not be homogeneous in all stem or progenitor cells.

Development of the hypothalamus: conservation, modification and innovation

“…Functional analyses have also revealed an inhibitory role for Wnt signaling in the formation and maintenance of radial glial progenitors. In zebrafish and mouse, ectopic Wnt activation leads to loss of hypothalamic radial glial cells Duncan et al, 2016). These data are all consistent with a model in which Wnt activity promotes an active state in radial glia, from which they undergo neurogenesis (Fig.…”

“…Progenitor cells first undergo a rapid proliferative expansion, followed by a period of asymmetric divisions that generate neural precursors, ending in the terminal differentiation of neurons (Duncan et al, 2016). Evolutionary conservation again exists for the molecular pathways that regulate these processes.…”

“…There is also wide variation in the scope of adult neurogenesis between species. In zebrafish, for example, the adult hypothalamus contains a high number of proliferating neural progenitors, which contribute to multiple lineages Duncan et al, 2016). However, the role of these cells in physiology and behavior is poorly understood.…”

Motor Behavior Mediated by Continuously Generated Dopaminergic Neurons in the Zebrafish Hypothalamus Recovers after Cell Ablation

“…The actual level of neurogenesis was likely even higher, due to the fact that progenitors becoming postmitotic before 8 dpf were not labeled with BrdU. In a separate study, we have also observed a transient increase in BrdU uptake by neural progenitors 2 days after ablation of th2+ neurons [23]. Together, these data show that th2+ neurons are capable of recovery after injury, similar to dopaminergic neurons in the mammalian olfactory bulb [24].…”

Hedgehog Signaling Regulates Neurogenesis in the Larval and Adult Zebrafish Hypothalamus

“…The zebrafish brain, which maintains up to 16 proliferative zones throughout life, has proven to be a powerful model for studying adult neurogenesis (Grandel et al, 2006;Schmidt et al, 2013;Anand and Mondal, 2017). Work in the zebrafish has defined a role for notch signaling in the telencephalon (Chapouton et al, 2010;Chapouton et al, 2011;Rothenaigner et al, 2011) and uncovered a key role for Wnt signaling in hypothalamic neurogenesis, with Wnt signaling being required for the formation of distinct neuronal subtypes and disruptions in Wnt-mediated hypothalamic proliferation leading to reduced growth and behavioral effects (Wang et al, 2012;Duncan et al, 2016;). Here we show that Hh signaling is both necessary and sufficient to regulate hypothalamic neural precursor proliferation throughout the life cycle, with Hh-responsive cells being a previously undescribed population of proliferative radial glia similar to transit amplifying (type III) neurogenic precursors.…”