Genetic Dissection of the Function of Hindbrain Axonal Commissures
Genetic Dissection of the Function of Hindbrain Axonal Commissures
复制标题
DOI：
10.1371/journal.pbio.1000325
复制
发表时间：
2010-03-01
期刊：
影响因子：
9.8
通讯作者：
Chedotal, Alain
中科院分区：
文献类型：
--
作者：
Renier, Nicolas;Schonewille, Martijn;Chedotal, Alain
在双边对称动物中，许多轴突穿过中枢神经系统的中线，形成明确的连合。尽管在哺乳动物中，前脑和视觉系统中连合的功能已被很好地确定，但其他轴向水平的功能尚不清楚。在这里，我们使用遗传方法剖析了几个后脑连合的功能。通过利用多个 Cre 转基因系，我们诱导了 Robo3 受体的位点特异性删除。这些线路随着感觉、运动和感觉运动系统中特定连合的破坏而发展，导致严重和永久性的功能缺陷。我们发现，菱形体 5 和菱形体 3 连合严重减少的小鼠分别具有异常的横向眼球运动和听觉脑干反应，而具有主要不交叉的攀爬纤维/浦肯野细胞投射的小鼠具有强烈的共济失调。令人惊讶的是，尽管改道的轴突仍然位于同侧，但它们仍然投射到适当的神经元目标。此外，一些Cre； Robo3 系列代表了可用于研究人类综合症的潜在模型，包括伴有进行性脊柱侧凸的水平凝视麻痹 (HGPPS)。据我们所知，这项研究是第一个将连合轴突引导缺陷与特定细胞和行为表型联系起来的研究之一。
In Bilateria, many axons cross the midline of the central nervous system, forming well-defined commissures. Whereas in mammals the functions of commissures in the forebrain and in the visual system are well established, functions at other axial levels are less clearly understood. Here, we have dissected the function of several hindbrain commissures using genetic methods. By taking advantage of multiple Cre transgenic lines, we have induced site-specific deletions of the Robo3 receptor. These lines developed with the disruption of specific commissures in the sensory, motor, and sensorimotor systems, resulting in severe and permanent functional deficits. We show that mice with severely reduced commissures in rhombomeres 5 and 3 have abnormal lateral eye movements and auditory brainstem responses, respectively, whereas mice with a primarily uncrossed climbing fiber/Purkinje cell projection are strongly ataxic. Surprisingly, although rerouted axons remain ipsilateral, they still project to their appropriate neuronal targets. Moreover, some Cre; Robo3 lines represent potential models that can be used to study human syndromes, including horizontal gaze palsy with progressive scoliosis (HGPPS). To our knowledge, this study is one of the first to link defects in commissural axon guidance with specific cellular and behavioral phenotypes.