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The mechanisms of language acquisition and evolution of mouse brain in Foxp2-KI mice

Foxp2-KI小鼠大脑语言习得和进化机制

基本信息

批准号：
21200011
负责人：
MOMOI Takashi
金额：
$ 18.72万
依托单位：
International University of Health and Welfare
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Innovative Areas (Research a proposed research project)
财政年份：
2009
资助国家：
日本
起止时间：
2009 至 2011
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21200011/
关键词：
進化言語言語障害 Broca FOXP2

项目摘要

The phenotype of speech-language disorder segregates as an autosomal dominant trait. One-half the members of the KE family with speech-language disorder have severe articulation difficulties accompanied by verbal and orofacial impairment. A missense mutation (R553H) in the forkhead domain of FOXP2 co-segregates with the affected members of the KE family. We have bridged the gap between the fMRI data and speech-language ability using knock-in mice with the Foxp2(R552H) mutation, Foxp2(R552H)-KI mice (Foxp2-KI mice), which is related to the FOXP2(R553H) mutation (PNAS 2008). Foxp2-KI mice exhibit impaired USV communication.Foxp2(R552H) increase cerebellar CNTNAP2 gene expression (Neurosci. Lett. 2012). FOXP2 promotes the nuclear translocation of POT1, but FOXP2(R553H), mutation related to speech-language disorder, partially prevents it.Cadm1-expressing synapses on Purkinje cell dendrites are involved in mouse ultrasonic vocalization activity (PLoS One. 2012). We generated transgenic mouse lines (Pcp2-FOXP2-myc-Tg;FOXP2-Tg) that specifically express human FOXP2 in Purkinje cells, by using BAC transgenesis of Pcp2 gene and Foxp2(R552H)-KI/ Pcp2-FOXP2-myc-Tg mice (Foxp2-KI/FOXP2-Tg) by mating with Foxp2-KI mice and examined the effects of FOXP2 on the USV function and Purkinje cells.

言语语言障碍的表型分离为常染色体显性性状。KE家族中有一半患有语言障碍的成员有严重的发音困难，并伴有语言和面部障碍。FOXP2叉头结构域的错义突变（R553H）与KE家族的受影响成员共分离。我们利用Foxp2（R552H）突变敲入小鼠、Foxp2(R552H)-KI小鼠（Foxp2-KI小鼠）弥合了fMRI数据与语言能力之间的差距，Foxp2（R553H）突变与Foxp2（R553H）突变有关（PNAS 2008）。Foxp2-KI小鼠表现出USV通信受损。Foxp2（R552H）增加小脑CNTNAP2基因表达(神经科学。博士论文,2012)。FOXP2促进POT1的核易位，但与语言障碍相关的突变FOXP2（R553H）部分阻止了POT1的核易位。浦肯野细胞树突上表达cadm1的突触参与小鼠超声发声活动（PLoS One, 2012）。我们利用Pcp2基因的BAC转基因技术，通过与FOXP2 -KI小鼠交配，获得了在浦肯野细胞中特异性表达人FOXP2的转基因小鼠系（Pcp2-FOXP2-myc- tg;FOXP2- tg），并检测了FOXP2对USV功能和浦肯野细胞的影响。