Regulation of nuclei-specific retinogeniculate targeting

描述(申请人提供)：突触是神经元之间传递信息的场所，对大脑功能至关重要。即使是由疾病或神经创伤引起的轻微突触异常，也会导致毁灭性的神经疾病，这一事实突显了它们的重要性。因此，了解中枢神经系统突触是如何被靶向、组装和维持(或提炼)的，对于我们理解神经疾病是至关重要的。其中一组突触的形成和完善受到了相当大的关注，这些突触是在视网膜神经节细胞(RGC)、视网膜的输出神经元和大脑内的目标神经元之间形成的。在罗杰·斯佩里(Roger Sperry)的化学亲和力假说(该假说认为，区域化的化学线索直接绘制了大脑内RGC轴突的地形图)的推动下，许多研究小组寻找并确定了必要的化学/分子线索，以正确地从视网膜退出视网膜神经节细胞轴突，RGC轴突在视交叉的正确交叉，RGC轴突与非视网膜靶点的排斥，以及外侧膝状核(LGN)和上丘(SC)内RGC轴突的地形图。尽管取得了这些重大进展，但仍不清楚不同类别的视网膜神经节细胞(RGC)--其中有22多个--如何靶向大脑中功能不同的核。类特异性靶向RGC轴突的一个大脑区域是LGN，这是一个丘脑中继核，包含三个结构和功能不同的亚核：腹侧LGN和背侧LGN(分别为vLGN和dLGN)以及分隔它们的膝间小叶。由于不同类型的RGC靶向vLGN和IGL或dLGN，我们假设LGN中必须存在区域化的引导线索来指导轴突靶向。初步研究已经确定了几个潜在的指导信号，并证明了一个信号，细胞外基质分子reelin，是视黄原酸酯靶向所必需的。本研究的目的是通过RGC轴突直接确定LGN的核和类特异性靶标是否需要卷绕。此外，它还建议探索依赖于reelin的视黄醇原酸盐靶向的细胞和分子机制，以及在没有reelin的情况下出现的靶向缺陷的功能后果。综上所述，本文提出的研究将极大地提高我们对RGC回路形成的理解，并将为ECM蛋白在类特异性靶向RGC轴突中的作用提供新的线索。

DESCRIPTION (provided by applicant): Synapses, the sites that allow information to be passed between neurons, are essential for brain function. Their importance is highlighted by the fact that even minor synaptic abnormalities, caused by disease or neurotrauma, result in devastating neurological conditions. Understanding how CNS synapses are targeted, assembled and maintained (or refined) is therefore essential to our understanding of neurological disorders. One set of synapses whose formation and refinement has received considerable attention are those formed between retinal ganglion cells (RGCs), the output neurons of the retina, and target neurons within the brain. Spurred on by Roger Sperry's postulation of the chemoaffinity hypothesis (which postulated that regionalized chemical cues direct topographic mapping of RGC axons within the brain), many groups have searched for and identified chemical/molecular cues necessary for the correct exiting of retinal ganglion cell axons from the retina, the correct crossing of RGC axons at the optic chiasm, the repulsion of RGC axons from non-retinal targets, and the topographic mapping of RGC axons within the lateral geniculate nucleus (LGN) and superior colliculus (SC). Despite these monumental advances, it still remains unclear how different classes of retinal ganglion cells (RGCs) - of which there are more than 22 - target functionally distinct nuclei within the brain. One brain region where class-specific targeting of RGC axons is most evident is the LGN - a thalamic relay nucleus that contains three structurally and functionally distinct subnuclei: the ventral and dorsal LGN (vLGN and dLGN, respectively) and the intergeniculate leaflet that separates them. Since different classes of RGCs target either vLGN and IGL or dLGN, we hypothesized that regionalized guidance cues must exist in the LGN to direct axonal targeting. Preliminary studies have identified several potential guidance cues and have demonstrated that one cue, the extracellular matrix molecule reelin, is necessary for retinogeniculate targeting. The present proposal aims to directly determine whether reelin is necessary for nuclei- and class-specific target of the LGN by RGC axons. Additionally, it proposes to explore both the cellular and molecular mechanisms responsible for reelin-dependent retinogeniculate targeting and to the function consequences of targeting defects that arise in the absence of reelin. Together, the studies proposed here will substantially progress our understanding of retinogeniculate circuit formation and will shed new light on the role of ECM proteins in class-specific targeting of RGC axons.