Transducin and melanopsin independent phototransduction in postnatal retinal development

在所谓的KK小鼠中，视杆细胞和视锥细胞转导蛋白α亚单位的基因消融并没有像我们所做的那样使外层视网膜沉默。 发现视网膜内层神经元仍然对光线有强烈的反应。这种令人惊讶的非转导蛋白依赖性光 敏感性不依赖于内在光敏视网膜神经节细胞中的黑视蛋白信号传导。这个所谓的 在3 K小鼠中体现的“不依赖于转导素和黑视素的光转导（TMIP）”显然起作用。 通过一种未知的和潜在的新的视网膜信号机制。我们已经证明了TMIP产生的光 信号通过视网膜回路并能够驱动视网膜神经节细胞以赋予成像视觉。我们 假设TMIP发生在发育和成熟视杆和/或视锥光感受器中，由视色素介导 和三聚体G蛋白，并且对于正常的出生后视网膜发育是必不可少的。在Aim-1中，我们将研究 TMIP的起源，以确定杆和/或锥作为TMIP发生的候选地点的相对贡献。在 目的-2我们将测试已知的视觉色素在TMIP中的参与，以及三聚体G蛋白和其他候选的 信号分子/通路。目的-3是充分表征TMIP在光依赖性出生后视网膜病变中的作用。 在转导蛋白依赖性的常规光转导尚未出现的时候发展。本申请 包含新的发现、概念、材料和方法上的创新。意义在于推进 光传导和视网膜发育领域，与临床相关的解释奥秘， 涉及Gnat 2和Cnga 3突变的不完全人类全色盲。

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.