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新型FRMD7剪接变体的鉴定及两种FRMD7转录本在人NT2细胞分化过程中的功能分析。

Identification of a novel FRMD7 splice variant and functional analysis of two FRMD7 transcripts during human NT2 cell differentiation.

作者信息

Li Yingzhi, Pu Jiali, Liu Zhirong, Xu Shanhu, Jin FanYing, Zhu Lijun, Tian Jun, Luo Jianhong, Zhang Baorong

机构信息

Department of Neurology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

出版信息

Mol Vis. 2011;17:2986-96. Epub 2011 Nov 17.

PMID:22128244
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3224827/
Abstract

PURPOSE

FERM domain containing protein 7 (FRMD7) mutations are associated with X-linked idiopathic congenital nystagmus (ICN). The purpose of this study is to identify a novel splice variant of FRMD7 (FRMD7-S) in both humans and mice with a shortened exon 4 relative to the original form of FRMD7 (FRMD7-FL),and to detect the role of FRMD7-FL and FRMD7-S in the process of neuronal development.

METHODS

The splice variant of FRMD7 was identified by PCR. Expression levels of hFRMD7-FL and hFRMD7-S transcripts in developing human fetal brain were tested by RT-PCR, and expression levels in the human pluripotent embryonic carcinoma NTera 2/cl.D1 (NTERA-2; NT2) cell line with all-trans retinoic acid (ATRA) or bone morphogenetic protein-2 (BMP-2) treatment were tested by real-time qPCR. hemaglutinin (HA)-tagged recombinant plasmids DNA encoding hFRMD7-FL and Myc-tagged recombinant plasmids DNA encoding hFRMD7-S were used to transiently transfect the human NT2 cells. Further, immunofluorescence experiments were performed to determine the co-localization of the two fusion proteins. Finally, using co-immunoprecipitation analyses, we demonstrated that FRMD7-FL and FRMD7-S interacted with each other.

RESULTS

A novel splice variant of FRMD7 (FRMD7-S) with a shortened exon 4 relative to the original form of FRMD7 (FRMD7-FL) was identified from the cDNA of the human NT2 cell line and mouse fetal brain. The FRMD7 transcripts showed similar tissue distributions and were upregulated following all trans retinoic acid (ATRA)-induced differentiation of NT2 cells. FRMD7-FL and FRMD7-S co-localized and co-immunoprecipitated with each other. Further, overexpression of FRMD7-FL in NT2 cells resulted in altered neurite development and upregulation of FRMD7-S.

CONCLUSIONS

Although the significance of the 45 bp deletion remains unknown, our observations suggest that the FRMD7 isoforms may play a significant role during neuronal differentiation and development.

摘要

目的

含FERM结构域蛋白7（FRMD7）突变与X连锁特发性先天性眼球震颤（ICN）相关。本研究的目的是在人类和小鼠中鉴定一种新型的FRMD7剪接变体（FRMD7-S），其相对于原始形式的FRMD7（FRMD7-FL）外显子4缩短，并检测FRMD7-FL和FRMD7-S在神经元发育过程中的作用。

方法

通过PCR鉴定FRMD7的剪接变体。通过RT-PCR检测发育中的人类胎儿脑中hFRMD7-FL和hFRMD7-S转录本的表达水平，通过实时定量PCR检测经全反式维甲酸（ATRA）或骨形态发生蛋白-2（BMP-2）处理的人多能胚胎癌NTera 2/cl.D1（NTERA-2；NT2）细胞系中的表达水平。用编码hFRMD7-FL的血凝素（HA）标签重组质粒DNA和编码hFRMD7-S的Myc标签重组质粒DNA瞬时转染人NT2细胞。此外，进行免疫荧光实验以确定两种融合蛋白的共定位。最后通过免疫共沉淀分析，我们证明了FRMD7-FL和FRMD7-S相互作用。

结果

从人NT2细胞系和小鼠胎儿脑的cDNA中鉴定出一种新型的FRMD7剪接变体（FRMD7-S），其相对于原始形式的FRMD7（FRMD7-FL）外显子4缩短。FRMD7转录本显示出相似的组织分布，并且在NT2细胞经全反式维甲酸（ATRA）诱导分化后上调。FRMD7-FL和FRMD7-S相互共定位并进行免疫共沉淀。此外，在NT2细胞中过表达FRMD7-FL导致神经突发育改变和FRMD7-S上调。

结论

虽然45bp缺失的意义尚不清楚，但我们的观察结果表明，FRMD7异构体可能在神经元分化和发育过程中发挥重要作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e3a/3224827/08feecbd425a/mv-v17-2986-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e3a/3224827/11c61893d52d/mv-v17-2986-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e3a/3224827/d17b2fc6900d/mv-v17-2986-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e3a/3224827/80a84c4489f6/mv-v17-2986-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e3a/3224827/d02630dc9328/mv-v17-2986-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e3a/3224827/08feecbd425a/mv-v17-2986-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e3a/3224827/11c61893d52d/mv-v17-2986-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e3a/3224827/d17b2fc6900d/mv-v17-2986-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e3a/3224827/80a84c4489f6/mv-v17-2986-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e3a/3224827/d02630dc9328/mv-v17-2986-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e3a/3224827/08feecbd425a/mv-v17-2986-f5.jpg

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Hum Mol Genet. 2010 Jan 15;19(2):342-51. doi: 10.1093/hmg/ddp500. Epub 2009 Nov 5.
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