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When SPG11 is mutated, patients frequently present with spastic paraparesis, a thin corpus callosum, and cognitive impairment. We previously delineated a neurodegenerative phenotype in neurons of these patients. In the current study, we recapitulated early developmental phenotypes of SPG11 and outlined their cellular and molecular mechanisms in patient\u2010specific induced pluripotent stem cell (iPSC)\u2010derived cortical neural progenitor cells (NPCs).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We generated and characterized iPSC\u2010derived NPCs and neurons from 3 SPG11 patients and 2 age\u2010matched controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Gene expression profiling of SPG11\u2010NPCs revealed widespread transcriptional alterations in neurodevelopmental pathways. These include changes in cell\u2010cycle, neurogenesis, cortical development pathways, in addition to autophagic deficits. More important, the GSK3\u00df\u2010signaling pathway was found to be dysregulated in SPG11\u2010NPCs. Impaired proliferation of SPG11\u2010NPCs resulted in a significant diminution in the number of neural cells. The decrease in mitotically active SPG11\u2010NPCs was rescued by GSK3 modulation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>This iPSC\u2010derived NPC model provides the first evidence for an early neurodevelopmental phenotype in SPG11, with GSK3\u00df as a potential novel target to reverse the disease phenotype. Ann Neurol 2016;79:826\u2013840<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.24633","type":"journal-article","created":{"date-parts":[[2016,3,14]],"date-time":"2016-03-14T04:57:16Z","timestamp":1457931436000},"page":"826-840","source":"Crossref","is-referenced-by-count":46,"title":["GSK3\u00df\u2010dependent dysregulation of neurodevelopment in SPG11\u2010patient induced pluripotent stem cell model"],"prefix":"10.1002","volume":"79","author":[{"given":"Himanshu K.","family":"Mishra","sequence":"first","affiliation":[{"name":"IZKF Junior Research Group III and BMBF Research Group Neuroscience, Friedrich\u2010Alexander\u2010Universitaet Erlangen\u2010Nuernberg (FAU) Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iryna","family":"Prots","sequence":"additional","affiliation":[{"name":"IZKF Junior Research Group III and BMBF Research Group Neuroscience, Friedrich\u2010Alexander\u2010Universitaet Erlangen\u2010Nuernberg (FAU) Erlangen 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