Department of Maternofetal Medicine, Genetics and Reproduction, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, 41013 Seville, Spain.
Centre for Biomedical Network Research on Rare Diseases (CIBERER), 41013 Seville, Spain.
Int J Mol Sci. 2020 Nov 28;21(23):9061. doi: 10.3390/ijms21239061.
Hirschsprung disease (HSCR) is a neurocristopathy characterized by intestinal aganglionosis which is attributed to a failure in neural crest cell (NCC) development during the embryonic stage. The colonization of the intestine by NCCs is a process finely controlled by a wide and complex gene regulatory system. Several genes have been associated with HSCR, but many aspects still remain poorly understood. The present study is focused on deciphering the PAX6 interaction network during enteric nervous system (ENS) formation. A combined experimental and computational approach was performed to identify PAX6 direct targets, as well as gene networks shared among such targets as potential susceptibility factors for HSCR. As a result, genes related to PAX6 either directly ( and ) or indirectly (, , and ) were identified as putative genes associated with HSCR. Interestingly, is involved in the RET/GDNF/GFRA1 signaling pathway, one of the main pathways implicated in the disease. Our findings represent a new contribution to advance in the knowledge of the genetic basis of HSCR. The investigation of the role of these genes could help to elucidate their implication in HSCR onset.
先天性巨结肠症（HSCR）是一种神经嵴细胞病变，其特征为肠无神经节细胞，这归因于胚胎期神经嵴细胞（NCC）发育失败。NCC 对肠道的定殖是一个由广泛而复杂的基因调控系统精细控制的过程。已经有几个基因与 HSCR 相关，但许多方面仍然知之甚少。本研究专注于破译肠神经系统（ENS）形成过程中的 PAX6 相互作用网络。采用了一种结合实验和计算的方法来识别 PAX6 的直接靶标，以及这些靶标之间共享的基因网络，作为 HSCR 的潜在易感因素。结果表明，与 PAX6 直接相关的基因（和）或间接相关的基因（、、和）被鉴定为可能与 HSCR 相关的基因。有趣的是，参与 RET/GDNF/GFRA1 信号通路，该通路是该疾病主要涉及的通路之一。我们的发现代表了在 HSCR 遗传基础研究方面的新进展。这些基因的作用研究有助于阐明它们在 HSCR 发病中的作用。
