Robo1 regulates the development of major axon tracts and interneuron migration in the forebrain
Robo1 regulates the development of major axon tracts and interneuron migration in the forebrain
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DOI：
10.1242/dev.02379
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发表时间：
2006-06-01
期刊：
影响因子：
4.6
通讯作者：
Richards, Linda J.
中科院分区：
文献类型：
--
作者：
Andrews, William;Liapi, Anastasia;Richards, Linda J.
Slit基因编码分泌型配体，其调节轴突分支、连合轴突寻路以及神经元迁移。已鉴定出的Slit的主要受体是Robo（果蝇中的Roundabout）。为了研究前脑发育中的Slit信号传导，我们通过靶向删除Robo1基因的第5外显子构建了Robo1基因敲除小鼠。纯合子敲除小鼠在出生时死亡，但在产前表现出轴突寻路和皮质中间神经元迁移的重大缺陷。轴突寻路缺陷包括胼胝体和海马连合发育不全，以及皮质丘脑和丘脑皮质投射异常。Slit2和Slit1/2双突变体在胼胝体发育、皮质丘脑和丘脑皮质投射以及视束方面表现出畸形。在这些动物中，皮质丘脑轴突形成大的束状结构，在海马连合和前连合水平以及更靠后的内侧视前区异常穿过中线。在Robo1基因敲除小鼠中未观察到这种皮质丘脑投射的表型，相反，皮质丘脑和丘脑皮质轴突都比对照组至少提前1天异常到达各自的靶点。相比之下，在Slit突变体中，在发育过程中实际到达皮质的丘脑轴突更少。最后，显著更多的中间神经元（在E12.5和E15.5时多达两倍）迁移到Robo1基因敲除小鼠的皮质中，特别是在额叶和顶叶区域，但不在尾侧皮质。这些结果表明Robo1突变体具有独特的表型，其中一些与Slit突变体中描述的不同，这表明可能有其他配体、受体或受体伴侣参与Slit/Robo信号传导。
The Slit genes encode secreted ligands that regulate axon branching, commissural axon pathfinding and neuronal migration. The principal identified receptor for Slit is Robo ( Roundabout in Drosophila). To investigate Slit signalling in forebrain development, we generated Robo1 knockout mice by targeted deletion of exon 5 of the Robo1 gene. Homozygote knockout mice died at birth, but prenatally displayed major defects in axon pathfinding and cortical interneuron migration. Axon pathfinding defects included dysgenesis of the corpus callosum and hippocampal commissure, and abnormalities in corticothalamic and thalamocortical targeting. Slit2 and Slit1/2 double mutants display malformations in callosal development, and in corticothalamic and thalamocortical targeting, as well as optic tract defects. In these animals, corticothalamic axons form large fasciculated bundles that aberrantly cross the midline at the level of the hippocampal and anterior commissures, and more caudally at the medial preoptic area. Such phenotypes of corticothalamic targeting were not observed in Robo1 knockout mice but, instead, both corticothalamic and thalamocortical axons aberrantly arrived at their respective targets at least 1 day earlier than controls. By contrast, in Slit mutants, fewer thalamic axons actually arrive in the cortex during development. Finally, significantly more interneurons ( up to twice as many at E12.5 and E15.5) migrated into the cortex of Robo1 knockout mice, particularly in both rostral and parietal regions, but not caudal cortex. These results indicate that Robo1 mutants have distinct phenotypes, some of which are different from those described in Slit mutants, suggesting that additional ligands, receptors or receptor partners are likely to be involved in Slit/Robo signalling.