title: Rcan1 deficiency impairs neuronal migration and causes periventricular heterotopia.
abstract: Periventricular heterotopia (PH) is a cortical malformation characterized by aggregation of neurons lining the lateral ventricles due to abnormal neuronal migration. The molecular mechanism underlying the pathogenesis of PH is unclear. Here we show that Regulators of calcineurin 1 (Rcan1), a Down syndrome-related gene, plays an important role in radial migration of rat cortical neurons. Downregulation of Rcan1 by expressing shRNA impaired neural progenitor proliferation and led to defects in radial migration and PH. Two isoforms of Rcan1 (Rcan1-1 and Rcan1-4) are expressed in the rat brain. Migration defects due to downregulation of Rcan1 could be prevented by shRNA-resistant expression of Rcan1-1 but not Rcan1-4. Furthermore, we found that Rcan1 knockdown significantly decreased the expression level of Flna, an F-actin cross-linking protein essential for cytoskeleton rearrangement and cell migration, mutation of which causes the most common form of bilateral PH in humans. Finally, overexpression of FLNA in Rcan1 knockdown neurons prevented migration abnormalities. Together, these findings demonstrate that Rcan1 acts upstream from Flna in regulating radial migration and suggest that impairment of Rcan1-Flna pathway may underlie PH pathogenesis.
authors.affiliation: Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. Shanghai 200031, People's Republic of China, and University of Chinese Academy of Sciences, Shanghai 200031, People's Republic of China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. Shanghai 200031, People's Republic of China, and University of Chinese Academy of Sciences, Shanghai 200031, People's Republic of China.
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
authors.affiliation: Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. Shanghai 200031, People's Republic of China, and.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. Shanghai 200031, People's Republic of China, and University of Chinese Academy of Sciences, Shanghai 200031, People's Republic of China.
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.affiliation: Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. Shanghai 200031, People's Republic of China, and xiongzhiqi@ion.ac.cn.
authors.forename: Zhi-Qi
authors.initials: ZQ
authors.lastname: Xiong
mesh_terms: D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D015536:Down-Regulation; D064448:Filamins / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D058953:Neural Stem Cells / Q000378:metabolism* / Q000502:physiology; D054091:Periventricular Nodular Heterotopia / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D064448:Filamins; D047908:Intracellular Signaling Peptides and Proteins; D020033:Protein Isoforms; C548050:RCAN1 protein, rat
keywords: FilaminA; Rcan1; migration; periventricular heterotopia