Abstract

Heterogeneous astrocyte populations are defined by diversity in cellular environment, progenitor identity or function. Yet, little is known about the extent of the heterogeneity and how this diversity is acquired during development. To investigate the impact of TGF (transforming growth factor) β-signaling on astrocyte development in the telencephalon we deleted the TGFBR2 (transforming growth factor beta receptor 2) in early neural progenitor cells in mice using a FOXG1 (forkhead box G1)-driven CRE-recombinase. We used quantitative proteomics to characterize TGFBR2-deficient cells derived from the mouse telencephalon and identified differential protein expression of the astrocyte proteins GFAP (glial fibrillary acidic protein) and MFGE8 (milk fat globule-EGF factor 8). Biochemical and histological investigations revealed distinct populations of astrocytes in the dorsal and ventral telencephalon marked by GFAP or MFGE8 protein expression. The two subtypes differed in their response to TGFβ-signaling. Impaired TGFβ-signaling affected numbers of GFAP astrocytes in the ventral telencephalon. In contrast, TGFβ reduced MFGE8-expression in astrocytes deriving from both regions. Additionally, lineage tracing revealed that both GFAP and MFGE8 astrocyte subtypes derived partly from FOXG1-expressing neural precursor cells.

Highlights

  • The development of the vertebrate forebrain relies on a timely regulated specification of different neural cell types

  • We revealed that distinct astrocyte populations expressed MFGE8 or GFAP in the DT and ventral telencephalon (VT) and that they responded differently to TGFβ stimulation

  • To reveal global differences between the proteome of Tgfbr2-cKO and wildtype (WT) forebrains we applied SILAC and quantitative proteomics (Ong et al, 2002; Ong and Mann, 2006) with cultured neural progenitor cells isolated from E13.5 entire telencephalon

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Summary

Introduction

The development of the vertebrate forebrain relies on a timely regulated specification of different neural cell types During this process, symmetric and asymmetric divisions of radial glia cells (RGCs) lead to the generation of neurons, astrocytes and oligodendrocytes. Symmetric and asymmetric divisions of radial glia cells (RGCs) lead to the generation of neurons, astrocytes and oligodendrocytes Differentiation of these cell types is temporally regulated whereby neurogenesis precedes astrogliogenesis and oligodendrocyte formation (Sauvageot and Stiles, 2002; Miller and Gauthier, 2007; Pinto and Götz, 2007; Franco and Müller, 2013). TGFβ mediated control of differentiation underlies temporally and spatially restricted transcriptional programs

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