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

Abstract

AbstractA 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.