Department of Pharmacology, Georgetown University Medical Center, Washington, DC 20057, USA.
Proc Natl Acad Sci U S A. 2011 Jan 25;108(4):1669-74. doi: 10.1073/pnas.1004744108. Epub 2011 Jan 4.
In the peripheral nervous system, target tissues control the final size of innervating neuronal populations by producing limited amounts of survival-promoting neurotrophic factors during development. However, it remains largely unknown if the same principle works to regulate the size of neuronal populations in the developing brain. Here we show that neurotrophin signaling mediated by the TrkB receptor controls striatal size by promoting the survival of developing medium-sized spiny neurons (MSNs). Selective deletion of the gene for the TrkB receptor in striatal progenitors, using the Dlx5/6-Cre transgene, led to a hindpaw-clasping phenotype and a 50% loss of MSNs without affecting striatal interneurons. This loss resulted mainly from increased apoptosis of newborn MSNs within their birthplace, the lateral ganglionic eminence. Among MSNs, those expressing the dopamine receptor D2 (DRD2) were most affected, as indicated by a drastic loss of these neurons and specific down-regulation of the DRD2 and enkephalin. This specific phenotype of mutant animals is likely due to preferential TrkB expression in DRD2 MSNs. These findings suggest that neurotrophins can control the size of neuronal populations in the brain by promoting the survival of newborn neurons before they migrate to their final destinations.
在周围神经系统中，靶组织通过在发育过程中产生有限数量的促进生存的神经营养因子来控制支配神经元群体的最终大小。然而，同样的原则是否适用于调节发育中大脑中神经元群体的大小，在很大程度上仍然未知。在这里，我们发现由 TrkB 受体介导的神经营养因子信号通过促进发育中的中型棘突神经元（MSNs）的存活来控制纹状体的大小。使用 Dlx5/6-Cre 转基因，选择性地在纹状体祖细胞中删除 TrkB 受体基因，导致后爪紧握表型和 MSNs 的 50%损失，而不影响纹状体中间神经元。这种损失主要是由于新生 MSNs 在其发源地外侧神经节隆起中的凋亡增加所致。在 MSNs 中，表达多巴胺受体 D2（DRD2）的神经元受影响最大，这些神经元大量丢失，DRD2 和脑啡肽特异性下调。这些突变动物的特定表型可能是由于 DRD2 MSNs 中优先表达 TrkB。这些发现表明，神经营养因子可以通过促进新生神经元在迁移到最终目的地之前的存活来控制大脑中神经元群体的大小。
