Lefebvre Julie L, Zhang Yifeng, Meister Markus, Wang Xiaozhong, Sanes Joshua R
Department of Molecular and Cellular Biology and Center for Brain Science, Harvard University, Cambridge, MA 02138, USA.
Development. 2008 Dec;135(24):4141-51. doi: 10.1242/dev.027912.
Twenty-two tandemly arranged protocadherin-gamma (Pcdh-gamma) genes encode transmembrane proteins with distinct cadherin-related extracellular domains and a common intracellular domain. Genetic studies have implicated Pcdh-gamma genes in the regulation of neuronal survival and synapse formation. Because mice lacking the Pcdh-gamma cluster die perinatally, we generated conditional mutants to analyze roles of Pcdh-gamma genes in the development and function of neural circuits. Retina-specific deletion of Pcdh-gammas led to accentuation of naturally occurring death of interneurons and retinal ganglion cells (RGCs) during the first two postnatal weeks. Nonetheless, many neuronal subtypes formed lamina-specific arbors. Blocking apoptosis by deletion of the pro-apoptotic gene Bax showed that even neurons destined to die formed qualitatively and quantitatively appropriate connections. Moreover, electrophysiological analysis indicated that processing of visual information was largely normal in the absence of Pcdh-gamma genes. These results suggest that Pcdh-gamma genes are dispensable for elaboration of specific connections in retina, but play a primary role in sculpting neuronal populations to appropriate sizes or proportions during the period of naturally occurring cell death.
22个串联排列的原钙黏蛋白γ（Pcdh-γ）基因编码具有不同钙黏蛋白相关细胞外结构域和共同细胞内结构域的跨膜蛋白。遗传学研究表明Pcdh-γ基因参与神经元存活和突触形成的调控。由于缺乏Pcdh-γ基因簇的小鼠在围产期死亡，我们构建了条件性突变体来分析Pcdh-γ基因在神经回路发育和功能中的作用。视网膜特异性缺失Pcdh-γ会导致出生后前两周内中间神经元和视网膜神经节细胞（RGC）自然死亡加剧。尽管如此，许多神经元亚型仍形成了层特异性树突。通过缺失促凋亡基因Bax来阻断细胞凋亡表明，即使注定要死亡的神经元也能形成质量和数量上合适的连接。此外，电生理分析表明，在没有Pcdh-γ基因的情况下，视觉信息处理在很大程度上是正常的。这些结果表明，Pcdh-γ基因对于视网膜中特定连接的形成并非必需，但在自然发生的细胞死亡期间，在将神经元群体塑造到合适大小或比例方面发挥着主要作用。
