Renal agenesis and the absence of enteric neurons in mice lacking GDNF
Renal agenesis and the absence of enteric neurons in mice lacking GDNF
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DOI：
10.1038/382070a0
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发表时间：
1996-07-04
期刊：
影响因子：
64.8
通讯作者：
Barbacid, M
中科院分区：
文献类型：
--
作者：
Sanchez, MP;SilosSantiago, I;Barbacid, M
胶质细胞系衍生的神经营养因子（GDNF）（1）是培养的多巴胺能神经元和运动神经元的有效存活因子（1，2）。它还在体外保护这些神经元免于变性（3-9），并改善啮齿动物（10）和猴子（11）中帕金森病诱导的痴呆等症状。因此GDNF可能在帕金森病和肌萎缩侧索硬化症的治疗中具有有益作用。为了检查GDNF在哺乳动物神经系统发育中的生理作用，我们已经通过在胚胎干细胞中使用同源重组来删除GDNF表达的两个编码外显子中的每一个而产生了GDNF表达缺陷的小鼠（1），GDNF缺失的小鼠，不管它们的靶向突变如何，由于缺乏输尿管芽的诱导而显示出完全的肾发育不全，输尿管芽是肾发育的早期步骤，这些小鼠也没有肠神经元，这可能解释了观察到的幽门狭窄和十二指肠扩张，然而，GDNF基因的消融不影响多巴胺能神经元的分化和存活，至少在胚胎发育期间。
GLIAL-CELL-LINE-DERIVED neurotrophic factor (GDNF)(1) is a potent survival factor for dopaminergic neurons and motor neurons in culture(1,2). It also protects these neurons from degeneration in vitro(3-9), and improves symptoms like Parkinson's disease induced pharmacologically in rodents(10) and monkeys(11), Thus GDNF might have beneficial effects in the treatment of Parkinson's disease and amyotrophic lateral sclerosis, To examine the physiological role of GDNF in the development of the mammalian nervous system, we have generated mice defective in GDNF expression by using homologous recombination in embryonic stem cells to delete each of its two coding exons(1), GDNF-null mice, regardless of their targeted mutation, display complete renal agenesis owing to lack of induction of the ureteric bud, an early step in kidney development, These mice also have no enteric neurons, which probably explains the observed pyloric stenosis and dilation of their duodenum, However, ablation of the GDNF gene does not affect the differentiation and survival of dopaminergic neurons, at least during embryonic development.