Survival control of oligodendrocyte progenitor cells requires the transcription factor 4 during olfactory bulb development

Yilan Zhang,Yunli Xie,Yifan Zhao,Yuqun Cai,Yafei Wang,Xin Deng,Yubin Zhang

doi:10.1038/s41419-020-03371-3

Yilan Zhang, Yunli Xie + Show 5 more

Open Access

https://doi.org/10.1038/s41419-020-03371-3

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Journal: Cell Death & Disease	Publication Date: Jan 1, 2021
Citations: 5	License type: open-access

Affiliation: Fudan University, Zhongshan Hospital

Abstract

A proper number of oligodendrocytes in the nerve system is essential for neuronal functions. In the olfactory bulb (OB), enriched oligodendrocytes are crucial for olfactory information processing. However, how the precise number of oligodendrocytes in the OB is regulated remains elusive. Here we identified that the transcription factor 4 (Tcf4)-mediated cell death is essential for generating an appropriate number of oligodendrocyte progenitor cells (OPCs) and thereby oligodendrocytes in the OB. We showed that Nkx2.1-positive progenitors in the medial ganglionic eminence (MGE) and anterior entopeduncular area (AEP) provide the first source of OPCs in the OB. Conditional depletion of Tcf4 leads to an increase of OPCs in the OB, which is mediated by the suppression of programmed cell death. Furthermore, we showed that Tcf4 mediated OPC survival is cell-autonomous by transplantation assay. Mechanistically, we identified Bax/Bak as a potential key pathway to promote OPC elimination during OB development. Depletion of Bax/Bak in Nkx2.1 lineage results in an increase of OPCs in the OB. Mutations in TCF4 causes Pitt-Hopkins syndrome, a severe neurodevelopmental disorder. Thus, our findings reveal an important intrinsic mechanism underlying the survival control of OPCs in the OB and provide new insights into the pathogenesis of Pitt–Hopkins syndrome.

Highlights

A precise number of oligodendrocytes is essential for neuronal functions through the myelination of axons in the central nervous system (CNS)[1,2,3]
When stained the sections for Olig[2], a marker for oligodendrocyte precursor cells (OPCs) and mature oligodendrocytes, we found that all Olig2-positive cells were positive for GFP (Fig. 1a, b), suggesting that Nkx2.1-positive radial glial cells (RGCs) generate the first wave of OPCs in the olfactory bulb (OB)
When analyzed the OB at postnatal day 7 (P7), we found that most OPCs were derived from RGCs labeled at E12.5 (Fig. 1d, e)

Summary

Introduction

A precise number of oligodendrocytes is essential for neuronal functions through the myelination of axons in the central nervous system (CNS)[1,2,3]. Oligodendrocytes develop from oligodendrocyte precursor cells (OPCs), which originate from the radial glial cells (RGCs) of the ventricular zone in several regions of the embryonic brain[4]. Nkx2.1 in the ventricular zone of the MGE and AEP generates most of the interneurons in the cortex[12]. After differentiation, these interneurons migrate tangentially to the dorsal cortex to form connections with local projection neurons[13,14,15]. In addition to the production of interneurons, Nkx2.1-positive RGCs contribute to the generation of the first wave of OPCs which further differentiate into mature oligodendrocytes in the neocortex[6,16]. While extensive studies have focused on how OPCs are generated from Nkx2.1-positive RGCs in the neocortex, the contribution of these RGCs to the production of OPCs in the OB, the essential structure involved in olfaction, is largely unknown

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