Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, CH-8093 Zurich, Switzerland, FMI for Biomedical Research, Novartis Research Foundation, CH-4058 Basel, Switzerland, Institute of Anatomy, University of Zurich, CH-8057 Zurich, Switzerland, Institute of Zoology, Department of Biology, University of Fribourg, CH-1700 Fribourg, Switzerland, and Developmental Biology and Neonatal Medicine Program, H.B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202.
J Neurosci. 2014 Apr 23;34(17):6112-22. doi: 10.1523/JNEUROSCI.5212-13.2014.
Schwann cells, the myelinating glia of the peripheral nervous system (PNS), originate from multipotent neural crest cells that also give rise to other cells, including neurons, melanocytes, chondrocytes, and smooth muscle cells. The transcription factor Sox10 is required for peripheral glia specification. However, all neural crest cells express Sox10 and the mechanisms directing neural crest cells into a specific lineage are poorly understood. We show here that histone deacetylases 1 and 2 (HDAC1/2) are essential for the specification of neural crest cells into Schwann cell precursors and satellite glia, which express the early determinants of their lineage myelin protein zero (P0) and/or fatty acid binding protein 7 (Fabp7). In neural crest cells, HDAC1/2 induced expression of the transcription factor Pax3 by binding and activating the Pax3 promoter. In turn, Pax3 was required to maintain high Sox10 levels and to trigger expression of Fabp7. In addition, HDAC1/2 were bound to the P0 promoter and activated P0 transcription. Consistently, in vivo genetic deletion of HDAC1/2 in mouse neural crest cells led to strongly decreased Sox10 expression, no detectable Pax3, virtually no satellite glia, and no Schwann cell precursors in dorsal root ganglia and peripheral nerves. Similarly, in vivo ablation of Pax3 in the mouse neural crest resulted in strongly reduced expression of Sox10 and Fabp7. Therefore, by controlling the expression of Pax3 and the concerted action of Pax3 and Sox10 on their target genes, HDAC1/2 direct the specification of neural crest cells into peripheral glia.
许旺细胞（Schwann cells）是周围神经系统（peripheral nervous system，PNS）的髓鞘形成胶质细胞，起源于多能神经嵴细胞（neural crest cells），后者还能产生其他细胞，包括神经元、黑色素细胞、软骨细胞和平滑肌细胞。转录因子 Sox10 是周围神经胶质细胞特化所必需的。然而，所有的神经嵴细胞都表达 Sox10，而将神经嵴细胞定向到特定谱系的机制尚不清楚。我们在这里表明，组蛋白去乙酰化酶 1 和 2（histone deacetylases 1 and 2，HDAC1/2）对于神经嵴细胞特化为许旺细胞前体细胞和卫星胶质细胞是必不可少的，这些细胞表达其谱系髓鞘蛋白零（myelin protein zero，P0）和/或脂肪酸结合蛋白 7（fatty acid binding protein 7，Fabp7）的早期决定因素。在神经嵴细胞中，HDAC1/2 通过结合并激活 Pax3 启动子来诱导转录因子 Pax3 的表达。反过来，Pax3 被要求维持高 Sox10 水平并触发 Fabp7 的表达。此外，HDAC1/2 结合到 P0 启动子并激活 P0 转录。一致地，在小鼠神经嵴细胞中体内遗传缺失 HDAC1/2 导致 Sox10 表达显著降低，检测不到 Pax3，几乎没有卫星胶质细胞，也没有许旺细胞前体细胞在背根神经节和周围神经中。同样，在小鼠神经嵴细胞中体内消融 Pax3 导致 Sox10 和 Fabp7 的表达显著减少。因此，通过控制 Pax3 的表达以及 Pax3 和 Sox10 对其靶基因的协同作用，HDAC1/2 指导神经嵴细胞特化为周围神经胶质细胞。
