Downregulation of Protein Tyrosine Phosphatase Receptor Type R Accounts for the Progression of Hirschsprung Disease
Downregulation of Protein Tyrosine Phosphatase Receptor Type R Accounts for the Progression of Hirschsprung Disease
复制标题
R 型蛋白酪氨酸磷酸酶受体下调导致先天性巨结肠病的进展
DOI：
10.3389/fnmol.2019.00092
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发表时间：
2019-04-10
影响因子：
4.8
通讯作者：
Jiang, Xun
中科院分区：
文献类型：
--
作者：
Tian, Jiao;Zeng, Cheng;Jiang, Xun
先天性巨结肠是一种常见的肠神经系统发育障碍。然而，其发病机制尚未完全阐明。为了更好地了解HSCR的病因，本研究探讨了HSCR相关的蛋白酪氨酸磷酸酶受体（PTPRR）在ENS祖细胞多能性和ENS发育中的作用和机制。在本研究中，下调PTPRR在HSCR的表达，反映了芯片和实时PCR分析验证。此外，PTPRR蛋白主要表达于原代培养的ENS祖细胞（肠神经嵴细胞，ENCCs）的胞浆区，在分化诱导后表达明显减少，提示PTPRR蛋白在ENCCs中具有抗分化作用。进一步的研究采用腺病毒转染系统。遗传调节后，ENCC保持未分化的模式，即使在GDNF（胶质细胞系衍生的神经营养因子）介导的定向分化，以及显着增加EdU阳性免疫荧光的PTPRR过表达组，而发育的ENS是在PTPRR敲低胎儿肠道发育迟缓。此外，在PTPRR过表达组中，GDNF激活的ERK 1/2的表达在基因调控后显著降低，这提示PTPRR过表达可能是通过调节MAPK/ERK 1/2通路实现的。这些数据支持PTPRR可能通过抑制ENCC的外显分化和维持ENCC的增殖来保证一定数量的神经前体细胞，这被认为是ENCC的多能性，并最终参与ENS的发育。并建立了PTPRR蛋白作为MAPK/ERK 1/ERK的负调节因子。2信号级联在神经元分化，并证明其参与HSCR的病理生理。
Hirschsprung disease (HSCR) is a common developmental disorder of the enteric nervous system (ENS). However, the disease mechanisms have not been fully elucidated. To better understand the etiology of HSCR, the role and mechanism of HSCR associated PTPRR (protein tyrosine phosphatase receptor-type R) in the multipotency of ENS progenitors and ENS development were explored. In the present study, the downregulated PTPRR expression in HSCR was reflected by microarray and validated by real-time PCR analyses. Moreover, PTPRR protein was mainly expressed in the cytoplasmic area of primary cultured ENS progenitors (Enteric neural crest cells, ENCCs) and significantly decreased after differentiation induction, which implies the anti-differentiation role in ENCCs. Further study employed an adenovirus transfection system. After genetic modulation, the ENCCs maintained undifferentiated patterns even in GDNF (Glial cell-line derived neurotrophic factor)-mediated directional differentiation, as well as significantly increased EdU positive immunofluorescence in the PTPRR overexpressing group while the development of the ENS was stunted in the PTPRR knockdown fetal gut. Moreover, the expression of ERK1 /2 activated by GDNF was significantly decreased as reflected by western-blot or immunofluorescence analyses after genetic modulation in the PTPRR overexpressing group, which suggests the potential mechanism in regulating the MAPK/ERK1/2 pathway. Taken together, These data support the idea that PTPRR may ensure a certain number of neural precursor cells by inhibiting ENCC overt differentiation and maintaining ENCC proliferation, which is considered to be the multipotency of ENCCs, and eventually participate in the development of the ENS, and establish PTPRR protein as negative regulator of MAPK/ERK1/2 signaling cascades in neuronal differentiation and demonstrate their involvement in the pathophysiology of HSCR.