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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Cell. Neurosci. | doi: 10.3389/fncel.2019.00523

BMP2 is related to Hirschsprung's disease and required for enteric nervous system development

Sizhou Huang1, Yi Wang2, Lingfei Luo3, Xiaoqing Li2, Xianqing Jin2, Shuangshuang Li2, Xiaoping Yu1, Min Yang4 and  Zhenhua Guo2*
  • 1Chengdu Medical College, China
  • 2Children‘s Hospital of Chongqing Medical University, China
  • 3Southwest University, China
  • 4School of Laboratory Medicine, Chengdu Medical College, China

The enteric nervous system (ENS) is derived from neural crest cells (NCCs). Defects in ENS NCCs colonizing the intestines lead to an absence of enteric ganglia in the colon and results in Hirschsprung's disease (HSCR). Bone morphogenetic proteins (BMPs) play diverse roles in the proliferation, migration and survival of ENS NCCs; however, whether BMPs are involved in HSCR and the underlying mechanism remains largely unknown. In this study, we found that BMP2 expression is significantly decreased in HSCR patients. Further experiments demonstrated that BMP2 is involved in the regulation of NCC proliferation, migration and differentiation. In a detailed analysis of the role of BMP2 in HSCR development in vivo, we demonstrated that BMP2b regulates the proliferation, migration and differentiation of vagal NCCs in zebrafish and that BMP2b is required for intestinal smooth muscle development. In addition, we showed that BMP2b is involved in regulating the expression of glial cell line-derived neurotrophic factor (GDNF) in the intestine, which mediates the regulation of ENS development by BMP2b in zebrafish. These results highlight a central role of the BMP-GDNF cascade in intestinal patterning and ENS development. Our results further demonstrate the key role of BMP2 in the aetiology of HSCR in vitro and in vivo.

Keywords: BMP2 (bone morphogenetic protein 2), GDNF (glial cell line-derived neurotrophic factor), Enteric nervous system (ENS), development, Hirschsprung's disease (HSCR)

Received: 23 May 2019; Accepted: 07 Nov 2019.

Copyright: © 2019 Huang, Wang, Luo, Li, Jin, Li, Yu, Yang and Guo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Zhenhua Guo, Children‘s Hospital of Chongqing Medical University, Chongqing, 400000, Chongqing Municipality, China, zhguo@hospital.cqmu.edu.cn