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Errors in this process are among the mechanisms of primary hereditary microcephaly (MCPH), a group of disorders characterized by reduced brain size and intellectual disability. Biallelic citron rho-interacting serine\/threonine kinase (\n                    <jats:italic>CIT<\/jats:italic>\n                    ) missense variants that disrupt kinase function (\n                    <jats:italic>\n                      CIT\n                      <jats:sup>KI\/KI<\/jats:sup>\n                    <\/jats:italic>\n                    ) and frameshift loss-of-function variants (\n                    <jats:italic>\n                      CIT\n                      <jats:sup>FS\/FS<\/jats:sup>\n                    <\/jats:italic>\n                    ) are the genetic basis for MCPH17; however, the function of CIT catalytic activity in brain development and NPC cytokinesis is unknown. Therefore, we created the\n                    <jats:italic>\n                      Cit\n                      <jats:sup>KI\/KI<\/jats:sup>\n                    <\/jats:italic>\n                    mouse model and found that it did not phenocopy human microcephaly, unlike biallelic\n                    <jats:italic>\n                      Cit\n                      <jats:sup>FS\/FS<\/jats:sup>\n                    <\/jats:italic>\n                    animals. Nevertheless, both\n                    <jats:italic>Cit<\/jats:italic>\n                    models exhibited binucleation, DNA damage, and apoptosis. To investigate human-specific mechanisms of\n                    <jats:italic>CIT<\/jats:italic>\n                    microcephaly, we generated\n                    <jats:italic>\n                      CIT\n                      <jats:sup>KI\/KI<\/jats:sup>\n                    <\/jats:italic>\n                    and\n                    <jats:italic>\n                      CIT\n                      <jats:sup>FS\/FS<\/jats:sup>\n                    <\/jats:italic>\n                    human forebrain organoids. We found that\n                    <jats:italic>\n                      CIT\n                      <jats:sup>KI\/KI<\/jats:sup>\n                    <\/jats:italic>\n                    and\n                    <jats:italic>\n                      CIT\n                      <jats:sup>FS\/FS<\/jats:sup>\n                    <\/jats:italic>\n                    organoids lost cytoarchitectural complexity, transitioning from pseudostratified to simple neuroepithelium. This change was associated with defects that disrupted the polarity of NPC cytokinesis, in addition to elevating apoptosis. Together, our results indicate that both CIT catalytic and scaffolding functions in NPC cytokinesis are critical for human corticogenesis. Species differences in corticogenesis and the dynamic 3D features of NPC mitosis underscore the utility of human forebrain organoid models for understanding human microcephaly.\n                  <\/jats:p>","DOI":"10.1172\/jci175435","type":"journal-article","created":{"date-parts":[[2024,9,24]],"date-time":"2024-09-24T12:00:41Z","timestamp":1727179241000},"source":"Crossref","is-referenced-by-count":15,"title":["Modeling primary microcephaly with human brain organoids reveals fundamental roles of CIT kinase activity"],"prefix":"10.1172","volume":"134","author":[{"given":"Gianmarco","family":"Pallavicini","sequence":"first","affiliation":[{"name":"Neuroscience Institute Cavalieri Ottolenghi, Turin, Italy."},{"name":"Department of Neuroscience \u201cRita Levi Montalcini,\u201d University of Turin, Turin, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Moccia","sequence":"additional","affiliation":[{"name":"Department of Human Genetics 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