Hypothalamic Rax+ tanycytes contribute to tissue repair and tumorigenesis upon oncogene activation in mice

Wenhui Mu,Xize Guo,Si Li,Haoda Wu,Chong Liu,Gisela Helfer,Falong Lu,Qing-Feng Wu,Jingkai Xu,Zhenhua Chen,Lianyong Qiao

doi:10.1038/s41467-021-22640-z

Abstract

Hypothalamic tanycytes in median eminence (ME) are emerging as a crucial cell population that regulates endocrine output, energy balance and the diffusion of blood-born molecules. Tanycytes have recently been considered as potential somatic stem cells in the adult mammalian brain, but their regenerative and tumorigenic capacities are largely unknown. Here we found that Rax+ tanycytes in ME of mice are largely quiescent but quickly enter the cell cycle upon neural injury for self-renewal and regeneration. Mechanistically, Igf1r signaling in tanycytes is required for tissue repair under injury conditions. Furthermore, Braf oncogenic activation is sufficient to transform Rax+ tanycytes into actively dividing tumor cells that eventually develop into a papillary craniopharyngioma-like tumor. Together, these findings uncover the regenerative and tumorigenic potential of tanycytes. Our study offers insights into the properties of tanycytes, which may help to manipulate tanycyte biology for regulating hypothalamic function and investigate the pathogenesis of clinically relevant tumors.

Highlights

Hypothalamic tanycytes in median eminence (ME) are emerging as a crucial cell population that regulates endocrine output, energy balance and the diffusion of blood-born molecules
We show that Rax+ tanycytes in ME robustly transit from a quiescent to an active state for tissue regeneration when subjected to neural injury
Rax+ tanycytes are susceptible to Braf oncogene activation and display tumorigenic potential (Fig. 8)

Summary

Introduction

Hypothalamic tanycytes in median eminence (ME) are emerging as a crucial cell population that regulates endocrine output, energy balance and the diffusion of blood-born molecules. Tanycytes have recently been considered as potential somatic stem cells in the adult mammalian brain, but their regenerative and tumorigenic capacities are largely unknown. Braf oncogenic activation is sufficient to transform Rax+ tanycytes into actively dividing tumor cells that eventually develop into a papillary craniopharyngioma-like tumor Together, these findings uncover the regenerative and tumorigenic potential of tanycytes. The ultrastructural analysis identifies tanycytes as uniciliated ependymal cells[20], implicating a potentially different function from typical ependymal cells Another important characteristic of somatic stem cells is their tumor-initiating potential[15,21,22], but the tumorigenic capacity of tanycytes has never been reported. We thereby manipulated tanycyte biology and performed lineage tracing using RaxCreERT2 knock-in mice, and revealed that Rax+ tanycytes responded to neural injury for regeneration and contributed to tumorigenesis upon Braf oncogene activation

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