Institut für Biochemie, Emil-Fischer-Zentrum, Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
J Cell Biol. 2010 May 17;189(4):701-12. doi: 10.1083/jcb.200912142. Epub 2010 May 10.
Mutations in the transcription factor SOX10 cause neurocristopathies, including Waardenburg-Hirschsprung syndrome and peripheral neuropathies in humans. This is partly attributed to a requirement for Sox10 in early neural crest for survival, maintenance of pluripotency, and specification to several cell lineages, including peripheral glia. As a consequence, peripheral glia are absent in Sox10-deficient mice. Intriguingly, Sox10 continues to be expressed in these cells after specification. To analyze glial functions after specification, we specifically deleted Sox10 in immature Schwann cells by conditional mutagenesis. Mutant mice died from peripheral neuropathy before the seventh postnatal week. Nerve alterations included a thinned perineurial sheath, increased lipid and collagen deposition, and a dramatically altered cellular composition. Nerve conduction was also grossly aberrant, and neither myelinating nor nonmyelinating Schwann cells formed. Instead, axons of different sizes remained unsorted in large bundles. Schwann cells failed to develop beyond the immature stage and were unable to maintain identity. Thus, our study identifies a novel cause for peripheral neuropathies in patients with SOX10 mutations.
转录因子 SOX10 的突变会导致神经嵴病变，包括人类的 Waardenburg-Hirschsprung 综合征和周围神经病变。这部分归因于 Sox10 在早期神经嵴中对存活、多能性维持和向包括周围神经胶质在内的几种细胞谱系特化的要求。因此，Sox10 缺陷小鼠缺乏周围神经胶质细胞。有趣的是，Sox10 在这些细胞特化后仍持续表达。为了分析特化后的神经胶质功能，我们通过条件性突变特异性地在未成熟施万细胞中缺失 Sox10。突变小鼠在出生后第七周前死于周围神经病。神经改变包括神经外膜鞘变薄、脂质和胶原沉积增加以及细胞组成显著改变。神经传导也严重异常，既没有髓鞘形成细胞也没有非髓鞘形成细胞形成。相反，不同大小的轴突仍未分类地存在于大束中。施万细胞无法发育到成熟阶段以外，也无法维持其身份。因此，我们的研究确定了 SOX10 突变患者周围神经病变的一个新原因。
