Aberrant transcriptional networks in step-wise neurogenesis of paroxysmal kinesigenic dyskinesia-induced pluripotent stem cells
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Chun Li1, Yu Ma1, Kunshan Zhang4, Junjie Gu1, Fan Tang1, Shengdi Chen2,3, Li Cao2, Siguang Li4,5, Ying Jin1,3
1Laboratory of Molecular Developmental Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
2Department of Neurology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
3Key Laboratory of Stem Cell Biology, Center for The Excellence in Molecular and Cell Sciences, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
4Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
5Collaborative Innovation Center for Brain Science, Tongji University, Shanghai 200092, China
Li Cao, email: email@example.com
Siguang Li, email: firstname.lastname@example.org
Ying Jin, email: email@example.com
Keywords: paroxysmal kinesigenic dyskinesia (PKD), proline-rich transmembrane protein 2 (PRRT2), induced pluripotent stem cells (iPSCs), neural differentiation, transcriptome analysis
Received: April 10, 2015 Accepted: June 30, 2016 Published: July 18, 2016
Paroxysmal kinesigenic dyskinesia (PKD) is an episodic movement disorder with autosomal-dominant inheritance and marked variability in clinical manifestations.
Proline-rich transmembrane protein 2 (PRRT2) has been identified as a causative gene of PKD, but the molecular mechanism underlying the pathogenesis of PKD still remains a mystery. The phenotypes and transcriptional patterns of the PKD disease need further clarification. Here, we report the generation and neural differentiation of iPSC lines from two familial PKD patients with c.487C>T (p. Gln163X) and c.573dupT (p. Gly192Trpfs*8) PRRT2 mutations, respectively. Notably, an extremely lower efficiency in neural conversion from PKD-iPSCs than control-iPSCs is observed by a step-wise neural differentiation method of dual inhibition of SMAD signaling. Moreover, we show the high expression level of PRRT2 throughout the human brain and the expression pattern of PRRT2 in other human tissues for the first time. To gain molecular insight into the development of the disease, we conduct global gene expression profiling of PKD cells at four different stages of neural induction and identify altered gene expression patterns, which peculiarly reflect dysregulated neural transcriptome signatures and a differentiation tendency to mesodermal development, in comparison to control-iPSCs. Additionally, functional and signaling pathway analyses indicate significantly different cell fate determination between PKD-iPSCs and control-iPSCs. Together, the establishment of PKD-specific in vitro models and the illustration of transcriptome features in PKD cells would certainly help us with better understanding of the defects in neural conversion as well as further investigations in the pathogenesis of the PKD disease.
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