Department of Developmental Biology and Kent Waldrep Center for Basic Research on Nerve Growth and Regeneration, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Proc Natl Acad Sci U S A. 2012 Sep 18;109(38):15491-6. doi: 10.1073/pnas.1212899109. Epub 2012 Sep 4.
Neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), are associated with the physiology of the striatum and the loss of its normal functioning under pathological conditions. The role of BDNF and its downstream signaling in regulating the development of the striatum has not been fully investigated, however. Here we report that ablation of Bdnf in both the cortex and substantia nigra depletes BDNF in the striatum, and leads to impaired striatal development, severe motor deficits, and postnatal lethality. Furthermore, striatal-specific ablation of TrkB, the gene encoding the high-affinity receptor for BDNF, is sufficient to elicit an array of striatal developmental abnormalities, including decreased anatomical volume, smaller neuronal nucleus size, loss of dendritic spines, reduced enkephalin expression, diminished nigral dopaminergic projections, and severe deficits in striatal dopamine signaling through DARPP32. In addition, TrkB ablation in striatal neurons elicits a non-cell-autonomous reduction of tyrosine hydroxylase protein level in the axonal projections of substantia nigral dopaminergic neurons. Thus, our results establish an essential function for TrkB in regulating the development of striatal neurons.
神经营养因子，如脑源性神经营养因子（BDNF），与纹状体的生理学以及其在病理条件下正常功能的丧失有关。然而，BDNF 及其下游信号在调节纹状体发育中的作用尚未得到充分研究。在这里，我们报告说 Bdnf 在皮质和黑质中的缺失会耗尽纹状体中的 BDNF，导致纹状体发育受损、严重的运动缺陷和出生后死亡。此外，纹状体特异性敲除 BDNF 的高亲和力受体 TrkB，足以引起一系列纹状体发育异常，包括解剖体积减小、神经元核更小、树突棘丢失、脑啡肽表达减少、黑质多巴胺能投射减少以及通过 DARPP32 的纹状体多巴胺信号严重缺陷。此外，纹状体神经元中的 TrkB 缺失会引发黑质多巴胺能神经元轴突投射中酪氨酸羟化酶蛋白水平的非细胞自主降低。因此，我们的结果确立了 TrkB 在调节纹状体神经元发育中的重要功能。
