TGFβ signalling maintains Sox4+ astrocyte progenitors and restricts the early differentiation of BLBP+ astrocytes in the mouse dentate gyrus.

Abstract

Astrocytes in the mouse hippocampal dentate gyrus (DG) derive, at least in part, from BLBP+ cells, but the mechanism that controls the onset of their differentiation remains poorly understood. To address this, we first characterised the developmental dynamics of BLBP+ cells using Ki67 and the cyclin-dependent kinase inhibitor p57. Ki67+/BLBP+ proliferative progenitors peaked at P1 and declined by P3-P6, when p57+/BLBP+ early-differentiating astrocytes instead accumulated. This temporal switch prompted us to examine what maintains the proliferative pool and restricts premature differentiation. We identified Sox4, a downstream transcription factor of TGFβ signalling, as a selective marker of the undifferentiated astrocytic lineage in the developing DG. At E15-E17, Sox4 was co-expressed with BLBP and pVimentin in basal radial glia (bRG), and at P1-P6 with BLBP, Sox3 and Ki67 in proliferative glial progenitors including the Olig2+/BLBP+ astrocyte progenitors (ASPs) we recently identified. Our data further suggest that Sox4 marks ASPs but not either NeuroD+ neuronal progenitors or p57+/BLBP+ early-differentiating astrocytes. From P14 onwards, Sox4 expression persisted in a subpopulation of BLBP+ radial glia-like cells (RGLs) at the SGZ and in BLBP+ cells in the molecular layer. Together, these data suggest that Sox4 selectively marks BLBP+ glial progenitors (bRG, RGLs and ASPs) but not their differentiated progeny. Consistent with an autocrine TGFβ1-Sox4 pathway described in glioma-initiating cells, TGFβ1 was co-expressed with BLBP in bRG, RGLs and ASPs. Blockade of TGFβ signalling with SB431542 in DG explants depleted Sox4+ progenitors and, in turn, promoted the accumulation of p57+/BLBP+ astrocytes. Our data thus suggest that TGFβ signalling maintains Sox4+ progenitors and thereby restricts the early differentiation of BLBP+ astrocytes in the mouse DG.