Natarajan Dipa, McCann Conor, Dattani Justine, Pachnis Vassilis, Thapar Nikhil
Division of Molecular Neurobiology, MRC National Institute for Medical Research, London, United Kingdom.
Birth Defects Research Centre, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.
Front Mol Neurosci. 2022 May 27;15:832317. doi: 10.3389/fnmol.2022.832317. eCollection 2022.
The majority of the enteric nervous system is formed by vagal neural crest cells which enter the foregut and migrate rostrocaudally to colonise the entire length of the gastrointestinal tract. Absence of enteric ganglia from the distal colon are the hallmark of Hirschsprung disease, a congenital disorder characterised by severe intestinal dysmotility. Mutations in the receptor tyrosine kinase RET have been identified in approximately 50% of familial cases of Hirschsprung disease but the cellular processes misregulated in this condition remain unclear. By lineage tracing neural crest cells in mice homozygous for a knock-in allele of (, we demonstrate that normal activity of this receptor is required for the migration of enteric nervous system progenitors throughout the gut. In mutant mice, progenitors of enteric neurons fail to colonise the distal colon, indicating that failure of colonisation of the distal intestine is a major contributing factor for the pathogenesis of Hirschsprung disease. Enteric nervous system progenitors in the ganglionic proximal guts of mutant mice are also characterised by reduced proliferation and differentiation. These findings suggest that the functional abnormalities in Hirschsprung disease result from a combination of colonic aganglionosis and deficits in neuronal circuitry of more proximal gut segments. The reduced neurogenesis in the gut of mutants was reproduced in the multilineage enteric nervous system progenitors isolated from these animals. Correction of the molecular defects of such progenitors fully restored their neurogenic potential in culture. These observations enhance our understanding of the pathogenesis of Hirschsprung disease and highlight potential approaches for its treatment.
大多数肠神经系统由迷走神经嵴细胞形成，这些细胞进入前肠并沿头尾方向迁移，以在胃肠道的整个长度上定植。远端结肠缺乏肠神经节是先天性巨结肠病的标志，这是一种以严重肠道运动障碍为特征的先天性疾病。在大约50%的家族性先天性巨结肠病病例中已发现受体酪氨酸激酶RET发生突变，但这种情况下失调的细胞过程仍不清楚。通过对携带（）敲入等位基因的纯合小鼠中的神经嵴细胞进行谱系追踪，我们证明该受体的正常活性是肠神经系统祖细胞在整个肠道中迁移所必需的。在突变小鼠中，肠神经元祖细胞无法在远端结肠定植，这表明远端肠道定植失败是先天性巨结肠病发病机制的一个主要促成因素。突变小鼠神经节近端肠道中的肠神经系统祖细胞还具有增殖和分化减少的特征。这些发现表明，先天性巨结肠病的功能异常是由结肠无神经节症和更近端肠道节段神经元回路缺陷共同导致的。在从这些动物分离的多谱系肠神经系统祖细胞中再现了突变体肠道中神经发生减少的情况。纠正此类祖细胞的分子缺陷可在培养中完全恢复其神经发生潜能。这些观察结果增进了我们对先天性巨结肠病发病机制的理解，并突出了其潜在的治疗方法。
