Torroglosa Ana, Villalba-Benito Leticia, Fernández Raquel María, Moya-Jiménez María José, Antiñolo Guillermo, Borrego Salud
Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville, University Hospital Virgen del Rocío, CSIC, University of Seville, Seville 41013, Spain.
Center for Biomedical Network Research on Rare Diseases, Seville 41013, Spain.
Oncotarget. 2017 Nov 16;8(63):106443-106453. doi: 10.18632/oncotarget.22473. eCollection 2017 Dec 5.
Hirschsprung disease (HSCR, OMIM 142623) is a pathology that shows a lack of enteric ganglia along of the distal gastrointestinal tract. This aganglionosis is attributed to an abnormal proliferation, migration, differentiation and/or survival of enteric precursor cells (EPCs) derived from neural crest cells (NCCs) during the enteric nervous system (ENS) embryogenesis. DNMT3b methyltransferase is associated with NCCs development and has been shown to be implicated in ENS formation as well as in HSCR. In this study we have aimed to elucidate the specific mechanism underlying the DNMT3b role in such processes. We have performed the knockdown of expression (-KD) in enteric precursor cells (EPCs) to clarify its role on these cells . Moreover, we have analyzed several signaling pathways to determine the mechanisms responsible for the effect caused by -KD in EPCs. Our results seem to support that -KD promotes an increase EPCs proliferation that may be mediated by P53 and P21 activity, since both proteins were observed to be down-regulated in our -KD cultures. Moreover, we observed a down-regulation of and in HSCR patients. These results lead us to propose that DNMT3b could be involved in HSCR through P53 and P21 activity.
先天性巨结肠（HSCR，OMIM 142623）是一种在远端胃肠道出现肠神经节缺失的病理状况。这种神经节细胞缺失症归因于在肠神经系统（ENS）胚胎发育过程中，源自神经嵴细胞（NCCs）的肠前体细胞（EPCs）出现异常增殖、迁移、分化和/或存活。DNMT3b甲基转移酶与NCCs的发育相关，并且已被证明与ENS形成以及HSCR有关。在本研究中，我们旨在阐明DNMT3b在此类过程中作用的具体机制。我们在肠前体细胞（EPCs）中进行了表达敲低（-KD）以阐明其对这些细胞的作用。此外，我们分析了几种信号通路，以确定负责EPCs中-KD所造成影响的机制。我们的结果似乎支持-KD促进EPCs增殖增加，这可能由P53和P21的活性介导，因为在我们的-KD培养物中观察到这两种蛋白质均下调。此外，我们在HSCR患者中观察到了和的下调。这些结果使我们提出DNMT3b可能通过P53和P21的活性参与HSCR。
