Modeling the differential phenotypes of spinal muscular atrophy with high-yield generation of motor neurons from human induced pluripotent stem cells.
Spinal muscular atrophy (SMA) is a devastating motor neuron disease caused by mutations of the survival motor neuron 1 (SMN1) gene. SMN2, a paralogous gene to SMN1, can partially compensate for the loss of SMN1. On the basis of age at onset, highest motor function and SMN2 copy numbers, childhood-onset SMA can be divided into three types (SMA I-III). An inverse correlation was observed between SMN2 copies and the differential phenotypes of SMA. Interestingly, this correlation is not always absolute. Using SMA induced pluripotent stem cells (iPSCs), we found that the SMN was significantly decreased in both SMA III and SMA I iPSCs derived postmitotic motor neurons (pMNs) and γ-aminobutyric acid (GABA) neurons. Moreover, the significant differences of SMN expression level between SMA III (3 copies of SMN2) and SMA I (2 copies of SMN2) were observed only in pMNs culture, but not in GABA neurons or iPSCs. From these findings, we further discovered that the neurite outgrowth was suppressed in both SMA III and SMA I derived MNs. Meanwhile, the significant difference of neurite outgrowth between SMA III and SMA I group was also found in long-term cultures. However, significant hyperexcitability was showed only in SMA I derived mature MNs, but not in SMA III group. Above all, we propose that SMN protein is a major factor of phenotypic modifier. Our data may provide a new insight into recognition for differential phenotypes of SMA disease.
Department of Neurology and Institute of Neurology, First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China.
Xiang
X
Lin
Department of Neurology and Institute of Neurology, First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China.
Jin-Jing
JJ
Li
Institutes of Brain Science, Institute of Neurobiology, State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China.
Wen-Jing
WJ
Qian
Department of Neurology and Institute of Neurology, First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China.
Qi-Jie
QJ
Zhang
Institutes of Brain Science, Institute of Neurobiology, State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China.
Zhong-Feng
ZF
Wang
Department of Neurology and Institute of Neurology, First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China.
Ying-Qian
YQ
Lu
Department of Neurology and Institute of Neurology, First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China.
En-Lin
EL
Dong
Department of Neurology and Institute of Neurology, First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China.
Jin
J
He
Department of Neurology and Institute of Neurology, First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China.
Ning
N
Wang
Department of Anatomy, Histology & Embryology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Li-Xiang
LX
Ma
Department of Neurology and Institute of Neurology, First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China.|Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou 350005, China.
Wan-Jin
WJ
Chen
D015415:Biomarkers; D002454:Cell Differentiation; D065150:Cellular Reprogramming; D055724:Electrophysiological Phenomena; D005260:Female; D059330:GABAergic Neurons / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D008297:Male; D009046:Motor Neurons / Q000166:cytology* / Q000378:metabolism*; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009154:Mutation; D016501:Neurites / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics / Q000378:metabolism
D015415:Biomarkers; D055533:Survival of Motor Neuron 1 Protein
induced pluripotent stem cells (iPSCs) derived enriched motor neurons (MNs); neurite outgrowth; neuronal activity; spinal muscular atrophy (SMA); survival motor neuron (SMN) protein