Transducin and melanopsin independent phototransduction in postnatal retinal development

在所谓的KK小鼠中，视杆和视锥转导蛋白α亚单位的遗传消融并不像我们所说的那样使外视网膜沉默 已经发现视网膜内部的神经元仍然对光做出强有力的反应。这种令人惊讶的不依赖于转导蛋白的光 敏感度并不依赖于视网膜神经节细胞中的黑素信号。这就是所谓的 3K小鼠体内的“转导和黑素非依赖性光转导(TMIP)”明显起作用 通过视网膜中一种未知的和潜在的新的信号机制。我们已经证明了TMIP产生的光 信号通过视网膜回路，能够驱动视网膜神经节细胞提供成像视觉。我们 假设TMIP发生在发育和成熟的视杆和/或视锥感光细胞中，由视觉色素介导 和三聚体G蛋白，对正常的出生后视网膜发育是不可或缺的。在AIM-1中，我们将研究细胞 TMIP的来源确定杆和/或锥体作为发生TMIP的候选场地的相对贡献。在……里面 AIM-2我们将测试已知的视觉色素参与TMIP，以及三聚体G蛋白和其他候选蛋白 信号分子/通路。目的-3是全面描述TMIP在光依赖的出生后视网膜中的作用 在依赖转导蛋白的常规光转导尚未出现的时候发育。此应用程序 包含新的发现、概念、材料和方法创新。意义在于推进 光传导和视网膜发育领域，与解释有关的谜团具有临床意义 涉及Gnat2和CnGa3突变的不完全性人类色觉障碍。

Genetic ablations of rod and cone transducin alpha subunits in the so-called KK mice do not silent the outer retina as we have found that inner retinal neurons still robustly respond to light. This surprised transducin-independent light sensitivity does not depend on melanopsin signaling in intrinsically photosensitive retinal ganglion cells. This so-named “transducin- and melanopsin-independent phototransduction (TMIP)” embodied in the 3K mice apparently works through an unknown and potentially novel signaling mechanism in retina. We have shown that TMIP-generated light signal passes through retinal circuit and is capable of driving retinal ganglion cells to confer image-forming vision. We hypothesize that TMIP occurs in developing and mature rod and/or cone photoreceptors, mediated by visual pigment and trimeric G-proteins, and indispensable for normal postnatal retinal development. In Aim-1 we will study the cellular origin of TMIP to determining relative contributions of rod and/or cone as candidate venue where TMIP takes place. In Aim-2 we will test the involvement of known visual pigments in TMIP, as well as trimeric G-proteins and other candidate signaling molecules/pathways. Aim-3 is to fully characterize TMIP’s role in light-dependent postnatal retinal development at times when transducin-dependent conventional phototransduction is yet to emerge. This application contains novel findings, conceptual, material and methodological innovations. Significance lies in the advancement of the phototransduction and retinal development fields, with clinical relevance in explaining mysteries concerning incomplete human achromatopsia involving Gnat2 and Cnga3 mutations.