Huang Yuanyun, Li Can, Desingu Rajan Ayyappa Raja, Bronner Marianne E
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125.
Proc Natl Acad Sci U S A. 2025 Aug 19;122(33):e2510548122. doi: 10.1073/pnas.2510548122. Epub 2025 Aug 11.
The vertebrate enteric nervous system (ENS) is derived from vagal neural crest cells, which enter the foregut as progenitors that migrate from rostral to caudal to populate the entire length of the gut. Here, we show that transcription factors and , zebrafish orthologs of the human gene, are highly expressed in neural crest cells transitioning from progenitors to differentiating neuronal subtypes. Accordingly, CRISPR-Cas9 depletion shows that loss of paralogs reduces the number of neurons that express the inhibitory motor neuron marker without affecting cell proliferation or death. Transcription factor footprinting analysis of open chromatin regions identified by ATAC-seq reveals Sox11 binding sites in the enhancer. Furthermore, mutational analysis shows these binding sites are required for mediating enhancer-driven reporter expression. Taken together, our results demonstrate an important and previously unrecognized role for and in neuronal subtype specification in the developing zebrafish ENS.
脊椎动物的肠神经系统(ENS)起源于迷走神经嵴细胞,这些细胞以前体细胞的形式进入前肠,从前向后迁移,遍布肠道全长。在这里,我们表明,转录因子 和 (人类 基因的斑马鱼直系同源物)在从前体细胞过渡到分化神经元亚型的神经嵴细胞中高度表达。相应地,CRISPR-Cas9基因敲除表明, 旁系同源物的缺失减少了表达抑制性运动神经元标志物 的神经元数量,而不影响细胞增殖或死亡。对通过ATAC-seq鉴定的开放染色质区域进行转录因子足迹分析,揭示了 增强子中的Sox11结合位点。此外,突变分析表明,这些结合位点是介导增强子驱动的报告基因表达所必需的。综上所述,我们的结果证明了 和 在发育中的斑马鱼ENS神经元亚型特化中具有重要且以前未被认识到的作用。