Regulation of nuclei-specific retinogeniculate targeting

描述（由申请人提供）：突触是允许信息在神经元之间传递的位置，对大脑功能至关重要。由于疾病或神经创伤引起的即使是轻微的突触异常，也会导致毁灭性的神经系统疾病，这一事实突出了它们的重要性。因此，了解中枢神经系统突触是如何定位、组装和维持（或完善）的，对我们理解神经系统疾病至关重要。视网膜神经节细胞（RGCs）、视网膜的输出神经元和大脑内的目标神经元之间形成的一组突触的形成和完善受到了相当大的关注。在罗杰·斯佩里（Roger Sperry）的化学亲和假说（该假说假设区域化的化学线索直接绘制大脑内RGC轴突的地形图）的假设的推动下，许多研究小组已经寻找并确定了视网膜神经节细胞轴突从视网膜正确退出、RGC轴突在视交叉处正确交叉、RGC轴突从非视网膜目标排斥所必需的化学/分子线索。以及外侧膝状核（LGN）和上丘（SC）内RGC轴突的地形测绘。尽管取得了这些巨大的进步，但人们仍然不清楚不同种类的视网膜神经节细胞（RGCs）——其中有超过22种——是如何针对大脑中功能不同的细胞核的。RGC轴突的类别特异性靶向最明显的一个大脑区域是LGN -一个丘脑中继核，包含三个结构和功能不同的亚核：腹侧和背侧LGN（分别为vLGN和dLGN）以及将它们分开的束间小叶。由于不同类型的RGCs分别靶向vLGN、IGL或dLGN，我们假设LGN中一定存在区域化的引导信号来指导轴突靶向。初步研究已经确定了几种潜在的引导信号，并证明其中一种信号，即细胞外基质分子reelin，是视网膜新生细胞靶向所必需的。本研究旨在通过RGC轴突直接确定reelin对于LGN的核特异性和类特异性靶标是否必要。此外，该研究还提出了探索reelin依赖性维甲酸靶向的细胞和分子机制，以及在缺乏reelin的情况下靶向缺陷的功能后果。总之，本文提出的研究将极大地推进我们对视黄酸环回路形成的理解，并将揭示ECM蛋白在RGC轴突特异性靶向中的作用。

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.