Genetics of mirror movements identifies a multifunctional complex required for Netrin-1 guidance and lateralization of motor control.
Genetics of mirror movements identifies a multifunctional complex required for Netrin-1 guidance and lateralization of motor control.
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DOI：
10.1126/sciadv.add5501
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发表时间：
2023-05-12
期刊：
影响因子：
13.6
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中科院分区：
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镜像运动障碍（MM）的特征是身体一侧的不自主运动反映了另一侧的有意运动。我们对一个常染色体显性遗传MM家族进行了遗传学鉴定，并将RhoGEF基因ARHGEF 7确定为MM的候选基因。我们发现Arhgef 7和它的伴侣Git 1直接与Dcc结合。Dcc是Netrin-1的受体，Netrin-1是一种将连合轴突吸引到中线的轴突引导线索，促进轴突束的中线交叉。我们发现，Arhgef 7和Git 1是Netrin-1介导的轴突导向所需的，并作为一个多功能的效应复合物。Arhgef 7/Git 1激活Rac 1和Cdc 42并抑制Netrin-1下游的Arf 1。此外，Arhgef 7/Git 1通过Arf 1介导Netrin-1诱导的细胞表面Dcc增加。Arhgef 7杂合子小鼠在连合轴突轨迹中存在缺陷，并且在熟练行走过程中增加了对称的爪放置，这是一种MM样表型。因此，我们已经描绘了ARHGEF 7突变如何导致MM。ARHGEF 7在镜像运动中突变，并且是Netrin-1/DCC轴突指导所需的多功能复合物的组成部分。
Mirror movements (MM) disorder is characterized by involuntary movements on one side of the body that mirror intentional movements on the opposite side. We performed genetic characterization of a family with autosomal dominant MM and identified ARHGEF7, a RhoGEF, as a candidate MM gene. We found that Arhgef7 and its partner Git1 bind directly to Dcc. Dcc is the receptor for Netrin-1, an axon guidance cue that attracts commissural axons to the midline, promoting the midline crossing of axon tracts. We show that Arhgef7 and Git1 are required for Netrin-1–mediated axon guidance and act as a multifunctional effector complex. Arhgef7/Git1 activates Rac1 and Cdc42 and inhibits Arf1 downstream of Netrin-1. Furthermore, Arhgef7/Git1, via Arf1, mediates the Netrin-1–induced increase in cell surface Dcc. Mice heterozygous for Arhgef7 have defects in commissural axon trajectories and increased symmetrical paw placements during skilled walking, a MM-like phenotype. Thus, we have delineated how ARHGEF7 mutation causes MM. ARHGEF7 is mutated in mirror movements and is a component of a multifunctional complex required for Netrin-1/DCC axon guidance.
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