A Critical Cell-Intrinsic Role for Serum Response Factor in Glial Specification in the CNS

Abstract

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-NestincKO) 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.

Regulation of serum response factor by miRNA‐200 and miRNA‐9 modulates oligodendrocyte progenitor cell differentiation

“…Thus, the present study indicates that overexpression of SRF promotes oligodendrocyte maturation. Since the original submission of our study, Lu and Ramanan have shown that knockout of Srf in nestin expressing neural progenitor cells causes a 50% reduction of OPCs in postnatal mice (Lu and Ramanan, 2012). Our data corroborate and add to their observation by showing that SRF is likely involved in the transition from early stage progenitor to mature OL, given that we observed the strongest colocalization of SRF with CNPase in vivo ; during maturation of OLs, CNPase expression is apparent during the transition from OPC to mature OL, followed by MBP and APC expression, with some temporal overlap evident (Scherer et al, 1994, Wada et al, 2000, See et al, 2004).…”

Glia in mammalian development and disease

“…During this time, numerous secreted signals -notably Sonic hedgehog (Shh), fibroblast growth factors (FGFs), Wnts, Notch/Delta, bone morphogenetic proteins (BMPs) and cytokinesact together to control cell fate spatially and temporally, leading to the presence of specific domains that selectively generate either astrocytes or OPCs (Rowitch and Kriegstein, 2010;Zuchero and Barres, 2013). Key transcription factors involved at this time include Sox9, nuclear factor I and serum response factor for general gliogenesis, and Olig1/Olig2 for OPC production (Rowitch and Kriegstein, 2010;Lu and Ramanan, 2012). Interestingly, astrocytes generated in distinct regions have important functional differences that are just beginning to be revealed (reviewed by Molofsky and Deneen, 2015).…”

Towards a better understanding of cognitive behaviors regulated by gene expression downstream of activity-dependent transcription factors

“…SRF has distinct roles in glial cells and neurons. SRF is implicated in glial specification (Lu & Ramanan, 2012) and SRF in astrocytes may modulate ocular dominance plasticity (Paul et al, 2010). In neurons, SRF is not essential for survival but is critical for induction and maintenance of LTP (Ramanan et al, 2005) and maintenance of LTD (Etkin et al, 2006;Smith-Hicks et al, 2010).…”