Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China.
Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China.
Int J Mol Sci. 2023 Apr 4;24(7):6700. doi: 10.3390/ijms24076700.
Insights into the role of microRNAs (miRNAs) in disease pathogenesis have made them attractive therapeutic targets, and numerous miRNAs have been functionally linked to Hirschsprung disease (HSCR), a life-threatening genetic disorder due to defective migration, proliferation, and colonization of enteric neural crest cells (ENCCs) in the gut. Recent studies have demonstrated that miR-424 strongly inhibits migration in a variety of cell types and its potential target is essential for neural crest cell development. We therefore sought to interrogate how miR-424 and contribute to the pathogenesis of HSCR. We utilized HSCR cases and human neural cells to evaluate the miR-424-mediated regulation of RICTOR and the downstream AKT phosphorylation. We further developed an ex vivo model to assess the effects of miR-424 on ENCC migration and proliferation. Then, single-cell atlases of gene expression in both human and mouse fetal intestines were used to determine the characteristics of and expression in the developing gut. Our findings demonstrate that miR-424 levels are markedly increased in the colonic tissues of patients with HSCR and that it regulates human neural cell migration by directly targeting . Up-regulation of miR-424 leads to decreased AKT phosphorylation levels in a RICTOR-dependent manner, and this, in turn, impairs ENCC proliferation and migration in the developing gut. Interestingly, we further identified prominent and expressions in the enteric neurons and other types of enteric neural cells in human and mouse fetal intestines. Our present study reveals the role of the miR-424/RICTOR axis in HSCR pathogenesis and indicates that miR-424 is a promising candidate for the development of targeted therapies against HSCR.
miRNAs 在疾病发病机制中的作用的深入了解使其成为有吸引力的治疗靶点，许多 miRNAs 已被证明与先天性巨结肠（HSCR）功能相关，HSCR 是一种危及生命的遗传疾病，由于肠道中的肠神经嵴细胞（ENCC）迁移、增殖和定植缺陷所致。最近的研究表明，miR-424 强烈抑制多种细胞类型的迁移，其潜在的靶标对于神经嵴细胞的发育是必不可少的。因此，我们试图探究 miR-424 和 如何参与 HSCR 的发病机制。我们利用 HSCR 病例和人神经细胞来评估 miR-424 对 RICTOR 的调节及其下游 AKT 磷酸化作用。我们进一步开发了一种离体模型来评估 miR-424 对 ENCC 迁移和增殖的影响。然后，使用人胎和鼠胎肠的单细胞图谱来确定 和 在发育中的肠道中的表达特征。我们的研究结果表明，miR-424 在 HSCR 患者的结肠组织中表达水平显著增加，并且它通过直接靶向 来调节人神经细胞的迁移。miR-424 的上调以 RICTOR 依赖性方式导致 AKT 磷酸化水平降低，这反过来又损害了发育中的肠道中 ENCC 的增殖和迁移。有趣的是，我们还在人胎和鼠胎肠的肠神经元和其他类型的肠神经细胞中进一步鉴定出了显著的 和 表达。我们的研究揭示了 miR-424/RICTOR 轴在 HSCR 发病机制中的作用，并表明 miR-424 是针对 HSCR 开发靶向治疗的有前途的候选药物。
