A critical cell-intrinsic role for serum response factor in glial specification in the CNS

Astrocytes and oligodendrocytes play crucial roles in nearly every facet of nervous system development and function, including neuronal migration, synaptogenesis, synaptic plasticity, and myelination. Previous studies have widely characterized the signaling pathways important for astrocyte differentiation and unveiled a number of transcription factors that guide oligodendrocyte differentiation in the CNS. However, the identities of the transcription factors critical for astrocyte specification in the brain remain unknown. Here we show that deletion of the stimulus-dependent transcription factor, serum response factor (SRF), in neural precursor cells (NPCs) (Srf-Nestin-cKO) results in nearly 60% loss in astrocytes and 50% loss in oligodendrocyte precursors at birth. Cultured SRF-deficient NPCs exhibited normal growth rate and capacity to self-renew. However, SRF-deficient NPCs generated fewer astrocytes and oligodendrocytes in response to several lineage-specific differentiation factors. These deficits in glial differentiation were rescued by ectopic expression of wild-type SRF in SRF-deficient NPCs. Interestingly, ectopic expression of a constitutively active SRF (SRF-VP16) in NPCs augmented astrocyte differentiation in the presence of pro-astrocytic factors. However, SRF-VP16 expression in NPCs had an inhibitory effect on oligodendrocyte differentiation. In contrast, mice carrying conditional deletion of SRF in developing forebrain neurons (Srf-NEX-cKO) did not exhibit any deficits in astrocytes in the brain. Together, our observations suggest that SRF plays a critical cell-autonomous role in NPCs to regulate astrocyte and oligodendrocyte specification in vivo and in vitro.