Department of Biochemistry, University of Washington, Seattle, Washington, United States of America.
PLoS Genet. 2011 Aug;7(8):e1002239. doi: 10.1371/journal.pgen.1002239. Epub 2011 Aug 11.
The identity of the specific molecules required for the process of retinal circuitry formation is largely unknown. Here we report a newly identified zebrafish mutant in which the absence of the atypical cadherin, Celsr3, leads to a specific defect in the development of GABAergic signaling in the inner retina. This mutant lacks an optokinetic response (OKR), the ability to visually track rotating illuminated stripes, and develops a super-normal b-wave in the electroretinogram (ERG). We find that celsr3 mRNA is abundant in the amacrine and ganglion cells of the retina, however its loss does not affect synaptic lamination within the inner plexiform layer (IPL) or amacrine cell number. We localize the ERG defect pharmacologically to a late-stage disruption in GABAergic modulation of ON-bipolar cell pathway and find that the DNQX-sensitive fast b1 component of the ERG is specifically affected in this mutant. Consistently, we find an increase in GABA receptors on mutant ON-bipolar terminals, providing a direct link between the observed physiological changes and alterations in GABA signaling components. Finally, using blastula transplantation, we show that the lack of an OKR is due, at least partially, to Celsr3-mediated defects within the brain. These findings support the previously postulated inner retina origin for the b1 component and reveal a new role for Celsr3 in the normal development of ON visual pathway circuitry in the inner retina.
视网膜回路形成过程中所需的特定分子的身份在很大程度上是未知的。在这里，我们报告了一种新鉴定的斑马鱼突变体，该突变体中存在非典型钙粘蛋白 Celsr3 的缺失，导致内视网膜 GABA 能信号传递的发育出现特定缺陷。该突变体缺乏光动反应（OKR），即无法对旋转的照明条纹进行视觉跟踪的能力，并且在视网膜电图（ERG）中发展出超正常的 b 波。我们发现 celsr3 mRNA 在视网膜的无长突细胞和节细胞中大量存在，但其缺失并不影响内丛状层（IPL）内的突触分层或无长突细胞数量。我们通过药理学方法将 ERG 缺陷定位到 GABA 能对 ON-双极细胞通路的调制的晚期破坏，并发现该突变体中 DNQX 敏感的快速 b1 成分的 ERG 受到特异性影响。一致地，我们发现突变体 ON-双极细胞末端的 GABA 受体增加，为观察到的生理变化与 GABA 信号传导成分的改变之间提供了直接联系。最后，通过胚泡移植，我们表明 OKR 的缺乏至少部分归因于大脑中 Celsr3 介导的缺陷。这些发现支持了之前提出的 b1 成分起源于内视网膜的假设，并揭示了 Celsr3 在正常 ON 视觉通路回路发育中的新作用。
