Cardiovascular Research Institute, University of California, San Francisco, CA 94158-2517, USA.
Development. 2011 Jun;138(12):2555-65. doi: 10.1242/dev.056804.
Waardenburg syndromes are characterized by pigmentation and autosensory hearing defects, and mutations in genes encoding transcription factors that control neural crest specification and differentiation are often associated with Waardenburg and related disorders. For example, mutations in SOX10 result in a severe form of Waardenburg syndrome, Type IV, also known as Waardenburg-Hirschsprung disease, characterized by pigmentation and other neural crest defects, including defective innervation of the gut. SOX10 controls neural crest development through interactions with other transcription factors. The MADS box transcription factor MEF2C is an important regulator of brain, skeleton, lymphocyte and cardiovascular development and is required in the neural crest for craniofacial development. Here, we establish a novel role for MEF2C in melanocyte development. Inactivation of Mef2c in the neural crest of mice results in reduced expression of melanocyte genes during development and a significant loss of pigmentation at birth due to defective differentiation and reduced abundance of melanocytes. We identify a transcriptional enhancer of Mef2c that directs expression to the neural crest and its derivatives, including melanocytes, in transgenic mouse embryos. This novel Mef2c neural crest enhancer contains three functional SOX binding sites and a single essential MEF2 site. We demonstrate that Mef2c is a direct transcriptional target of SOX10 and MEF2 via this evolutionarily conserved enhancer. Furthermore, we show that SOX10 and MEF2C physically interact and function cooperatively to activate the Mef2c gene in a feed-forward transcriptional circuit, suggesting that MEF2C might serve as a potentiator of the transcriptional pathways affected in Waardenburg syndromes.
瓦登伯革综合征的特征是色素沉着和本体感觉听力缺陷，而控制神经嵴特化和分化的转录因子基因突变常与瓦登伯革和相关疾病有关。例如，SOX10 基因突变导致严重的瓦登伯革综合征 IV 型，也称为瓦登伯革-先天性巨结肠病，其特征是色素沉着和其他神经嵴缺陷，包括肠道神经支配缺陷。SOX10 通过与其他转录因子相互作用来控制神经嵴的发育。MADS 盒转录因子 MEF2C 是大脑、骨骼、淋巴细胞和心血管发育的重要调节剂，在神经嵴中对于颅面发育是必需的。在这里，我们确立了 MEF2C 在黑素细胞发育中的一个新作用。在小鼠的神经嵴中失活 Mef2c 会导致发育过程中黑素细胞基因的表达减少，并且由于分化缺陷和黑素细胞数量减少，出生时的色素沉着显著丧失。我们鉴定了一个 MEF2C 的转录增强子，该增强子指导在转基因小鼠胚胎中的神经嵴及其衍生物（包括黑素细胞）中的表达。这个新的 MEF2C 神经嵴增强子含有三个功能 SOX 结合位点和一个单一的必需 MEF2 位点。我们证明了 MEF2C 是 SOX10 和 MEF2 通过这个进化上保守的增强子的直接转录靶标。此外，我们表明 SOX10 和 MEF2C 物理相互作用并协同作用以激活前馈转录电路中的 Mef2c 基因，这表明 MEF2C 可能作为受瓦登伯革综合征影响的转录途径的增强子。
