Jain Sanjay, Golden Judith P, Wozniak David, Pehek Elizabeth, Johnson Eugene M, Milbrandt Jeffrey
Department of Medicine, Renal Division, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
J Neurosci. 2006 Oct 25;26(43):11230-8. doi: 10.1523/JNEUROSCI.1876-06.2006.
Glial cell-line derived neurotrophic factor (GDNF)-mediated RET tyrosine kinase signaling is implicated in the survival of several PNS and CNS neuronal populations that are important in the pathogenesis of several disorders including Parkinson's disease and drug addiction. However, it has been difficult to study these processes and the physiological importance of this pathway in adult mice because of the neonatal lethality of Gdnf and Ret null mice. We report successful creation of RET conditional reporter mice to investigate postnatal physiologic roles of RET and monitor the fate of RET-expressing cell types. To delete RET specifically in dopaminergic neurons and determine the physiologic requirement of RET in the maintenance of substantia nigra compacta (SNC) and ventral tegmental area (VTA), we bred the RET conditional mice with mice that specifically express Cre from the dopamine transporter (Dat) locus. A detailed morphometric and biochemical analysis including dopaminergic neuron number and size in SNC and VTA, and fiber density in the striatum and nucleus accumbens, and dopamine levels indicate that RET is not required for providing global trophic support to midbrain dopaminergic neurons in adult mice. Furthermore, RET deficiency in these neurons does not cause major sensorimotor abnormalities. Hence our results support the idea that RET signaling is not critical for the normal physiology of the SNC and VTA in adult mice.
胶质细胞源性神经营养因子（GDNF）介导的RET酪氨酸激酶信号传导与几种周围神经系统和中枢神经系统神经元群体的存活有关，这些神经元群体在包括帕金森病和药物成瘾在内的几种疾病的发病机制中起着重要作用。然而，由于Gdnf和Ret基因敲除小鼠的新生儿致死性，在成年小鼠中研究这些过程以及该信号通路的生理重要性一直很困难。我们报告成功创建了RET条件报告基因小鼠，以研究RET在出生后的生理作用，并监测表达RET的细胞类型的命运。为了在多巴胺能神经元中特异性删除RET，并确定RET在维持黑质致密部（SNC）和腹侧被盖区（VTA）中的生理需求，我们将RET条件小鼠与从多巴胺转运体（Dat）基因座特异性表达Cre的小鼠进行杂交。详细的形态计量学和生化分析，包括SNC和VTA中多巴胺能神经元的数量和大小、纹状体和伏隔核中的纤维密度以及多巴胺水平，表明RET对于成年小鼠中脑多巴胺能神经元的整体营养支持并非必需。此外，这些神经元中RET的缺乏不会导致主要的感觉运动异常。因此，我们的结果支持这样一种观点，即RET信号传导对成年小鼠SNC和VTA的正常生理功能并不关键。
