Sumoylation of FOXP2 Regulates Motor Function and Vocal Communication Through Purkinje Cell Development.
Sumoylation of FOXP2 Regulates Motor Function and Vocal Communication Through Purkinje Cell Development.
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DOI：
10.1016/j.biopsych.2016.02.008
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发表时间：
2017-02-01
影响因子：
10.6
通讯作者：
Konopka G
中科院分区：
文献类型：
--
作者：
Usui N;Co M;Harper M;Rieger MA;Dougherty JD;Konopka G
编码转录因子叉头盒P2（FOXP2）的基因突变会导致大脑发育异常，包括人类患者和啮齿动物模型中的灰质减少，以及言语和语言缺陷。然而，既没有探索FOXP2在脑（特别是小脑）中的区域特异性功能，也没有探索FOXP2在脑和病症中的任何翻译后修饰的作用。我们对FOXP2的SUMO化进行了生物化学表征，并分析了FOXP2在发育中的小鼠小脑中的区域特异性功能和SUMO化。使用子宫内电穿孔来操纵Foxp2的sumoylation状态以及体内小脑浦肯野细胞（PC）中Foxp2的表达水平，我们将小鼠小脑中Foxp2的表达降低了约40%。这种减少近似于在表现出言语和语言障碍的人类患者中观察到的单倍不足。我们在新生儿小脑中鉴定了K674（小鼠K673）处FOXP2的SUMO化。体外免疫共沉淀和体内共定位实验表明，PIAS 3作为SUMO E3连接酶的FOXP2类小泛素化。这种类小泛素化修饰通过FOXP2调节转录。我们证明，Foxp2类小泛素化是必要的调节小脑运动功能和声乐沟通，可能通过树突状生长和树枝状的PC在小鼠小脑。新生小鼠小脑Foxp2的SUMO化调节PC发育以及运动功能和声音交流，证明SUMO化调节哺乳动物行为的证据。
Mutations in the gene encoding the transcription factor forkhead box P2, FOXP2, result in brain developmental abnormalities including reduced gray matter in both human patients and rodent models, and speech and language deficits. However, neither the region-specific function of FOXP2 in the brain, in particular the cerebellum, nor the effects of any post-translational modifications of FOXP2 in the brain and disorders have been explored. We characterized sumoylation of FOXP2 biochemically, and analyzed the region-specific function and sumoylation of FOXP2 in the developing mouse cerebellum. Using in utero electroporation to manipulate the sumoylation-state of Foxp2 as well as Foxp2 expression levels in Purkinje cells (PCs) of the cerebellum in vivo, we reduced Foxp2 expression approximately 40% in the mouse cerebellum. Such a reduction approximates the haploinsufficiency observed in human patients who demonstrate speech and language impairments. We identified sumoylation of FOXP2 at K674 (K673 in mouse) in the cerebellum of neonates. In vitro co-immunoprecipitation and in vivo colocalization experiments suggest that PIAS3 acts as the SUMO E3 ligase for FOXP2 sumoylation. This sumoylation modifies transcriptional regulation by FOXP2. We demonstrate that Foxp2 sumoylation is required for regulation of cerebellar motor function and vocal communication, likely through dendritic outgrowth and arborization of PCs in the mouse cerebellum. Sumoylation of Foxp2 in neonatal mouse cerebellum regulates PC development as well as motor functions and vocal communication, demonstrating evidence for sumoylation in regulating mammalian behaviors.