Disturbances of colonic motility in mouse models of Hirschsprung's disease
Disturbances of colonic motility in mouse models of Hirschsprung's disease
复制标题
DOI：
10.1152/ajpgi.00558.2007
复制
发表时间：
2008-04-01
影响因子：
4.5
通讯作者：
Young, Heather M.
中科院分区：
文献类型：
--
作者：
Roberts, Rachael R.;Bornstein, Joel C.;Young, Heather M.
先天性巨结肠小鼠模型结肠动力障碍美国生理学杂志胃肠和肝脏生理学294：G996-G1008，2008年。首次发表于2008年2月14日; doi：10.1152/ajpgi。00558.2007.编码GDNF和内皮素-3（Et-3）信号通路成员的基因突变可导致先天性巨结肠病，这是一种与远端肠道中肠神经元缺失相关的先天性疾病。GDNF通过受体酪氨酸激酶Ret发出信号，Et-3通过内皮素受体B（Ednr B）发出信号。GDNF，Ret和Et-3单倍不足和Et-3无效突变对成年和发育中小鼠自发运动模式的影响进行了研究。利用录像技术构建了出生后和成年小鼠离体结肠自发收缩模式的时空图。在具有正常肠神经元数量的Ret（+/-）和Et- 3（+/-）小鼠中，结肠移行运动复合体（CMMC）在对照条件下和在抑制一氧化氮合酶（NOS）活性后显示出与野生型小鼠相似的性质。在Gdnf（+/-）小鼠的结肠和Et-3（+/-）小鼠的神经节区域中，肌间神经元数量减少50-60%。在Gdnf（+/-）小鼠中，存在CMMCs，但异常，并且含有NOS的肌间神经元的比例与野生型小鼠没有差异。在出生后Et-3（-/-）小鼠的神经节区，CMMCs缺失，肌间神经元中含有NOS的比例比野生型小鼠高100%以上。因此，GDNF（+/-）小鼠结肠和Et-3（+/-）小鼠神经节区的自发运动模式受损与肌间神经元密度降低相关。
Disturbances of colonic motility in mouse models of Hirschsprung's disease. Am J Physiol Gastrointest Liver Physiol 294: G996-G1008, 2008. First published February 14, 2008; doi:10.1152/ajpgi. 00558.2007. Mutations in genes encoding members of the GDNF and endothelin-3 (Et-3) signaling pathways can cause Hirschsprung's disease, a congenital condition associated with an absence of enteric neurons in the distal gut. GDNF signals through Ret, a receptor tyrosine kinase, and Et-3 signals through endothelin receptor B (Ednrb). The effects of Gdnf, Ret, and Et-3 haploinsufficiency and a null mutation in Et-3 on spontaneous motility patterns in adult and developing mice were investigated. Video recordings were used to construct spatiotemporal maps of spontaneous contractile patterns in colon from postnatal and adult mice in vitro. In Ret(+/-) and Et- 3(+/-) mice, which have normal numbers of enteric neurons, colonic migrating motor complexes (CMMCs) displayed similar properties under control conditions and following inhibition of nitric oxide synthase ( NOS) activity to wildtype mice. In the colon of Gdnf(+/-) mice and in the ganglionic region of Et-3(+/-) mice, there was a 50-60% reduction in myenteric neuron number. In Gdnf(+/-) mice, CMMCs were present, but abnormal, and the proportion of myenteric neurons containing NOS was not different from that of wild-type mice. In the ganglionic region of postnatal Et-3(-/-) mice, CMMCs were absent, and the proportion of myenteric neurons containing NOS was over 100% higher than in wild-type mice. Thus impairments in spontaneous motility patterns in the colon of Gdnf(+/-) mice and in the ganglionic region of Et-3(+/-) mice are correlated with a reduction in myenteric neuron density.