Sánchez M P, Silos-Santiago I, Frisén J, He B, Lira S A, Barbacid M
Department of Molecular Oncology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543, USA.
Nature. 1996 Jul 4;382(6586):70-3. doi: 10.1038/382070a0.
Glial-cell-line-derived neurotrophic factor (GDNF) is a potent survival factor for dopaminergic neurons and motor neurons in culture. It also protects these neurons from degeneration in vitro, and improves symptoms like Parkinson's disease induced pharmacologically in rodents and monkeys. 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. GDNF-null mice, regardless of their targeted mutation, display complete renal agencies 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.
胶质细胞源性神经营养因子（GDNF）是培养中的多巴胺能神经元和运动神经元的一种强效存活因子。它还能在体外保护这些神经元免于退化，并改善在啮齿动物和猴子身上通过药理学方法诱导的类似帕金森病的症状。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。为了研究GDNF在哺乳动物神经系统发育中的生理作用，我们通过在胚胎干细胞中进行同源重组以删除其两个编码外显子中的每一个，从而培育出GDNF表达缺陷的小鼠。无论其靶向突变如何，GDNF基因敲除小鼠均表现出完全的肾发育不全，这是由于缺乏输尿管芽的诱导，而输尿管芽诱导是肾脏发育的早期步骤。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，至少在胚胎发育期间，GDNF基因的缺失并不影响多巴胺能神经元的分化和存活。
