Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
J Neurosci. 2012 Jun 6;32(23):8012-23. doi: 10.1523/JNEUROSCI.5633-11.2012.
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.
星形胶质细胞和少突胶质细胞在神经系统发育和功能的几乎各个方面都起着至关重要的作用，包括神经元迁移、突触形成、突触可塑性和髓鞘形成。先前的研究广泛描述了对星形胶质细胞分化重要的信号通路，并揭示了许多指导中枢神经系统少突胶质细胞分化的转录因子。然而，对于大脑中星形胶质细胞特化所必需的转录因子的身份仍不清楚。在这里，我们表明在神经前体细胞（NPCs）中删除应激诱导转录因子血清反应因子（SRF）（Srf-Nestin-cKO）会导致出生时星形胶质细胞减少近 60%，少突胶质细胞前体细胞减少 50%。培养的 SRF 缺陷 NPCs 表现出正常的生长速度和自我更新能力。然而，SRF 缺陷 NPCs 在对几种谱系特异性分化因子的反应中产生的星形胶质细胞和少突胶质细胞较少。在 SRF 缺陷 NPCs 中异位表达野生型 SRF 可挽救这些神经胶质分化缺陷。有趣的是，在存在促星形胶质细胞因子的情况下，NPCs 中组成型激活的 SRF（SRF-VP16）的异位表达增强了星形胶质细胞分化。然而，SRF-VP16 在 NPCs 中的表达对少突胶质细胞分化具有抑制作用。相比之下，在发育中的大脑神经元中携带 SRF 条件性缺失的小鼠（Srf-NEX-cKO）在大脑中没有表现出任何星形胶质细胞缺陷。总之，我们的观察结果表明，SRF 在 NPCs 中发挥关键的细胞自主作用，以调节体内和体外星形胶质细胞和少突胶质细胞的特化。
