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Mutations in upstream elements regulating the ERK pathway are genetically linked to autism and other disorders of cognition including the neuro-cardio-facial cutaneous syndromes and copy number variations. We report that a murine model of human<jats:italic>16p11.2<\/jats:italic>deletion exhibits a reduction in brain size and perturbations in cortical cytoarchitecture. We observed enhanced progenitor proliferation and premature cell cycle exit, which are a consequence of altered levels of downstream ERK effectors cyclin D1 and p27<jats:sup>Kip1<\/jats:sup>during mid-neurogenesis. The increased progenitor proliferation and cell cycle withdrawal resulted in premature depletion of progenitor pools, altering the number and frequency of neurons ultimately populating cortical lamina. Specifically, we found a reduced number of upper layer pyramidal neurons and an increase in layer VI corticothalamic projection neurons, reflecting the altered cortical progenitor proliferation dynamics in these mice. Importantly, we observed a paradoxical increase in ERK signaling in mid-neurogenesis in the<jats:italic>16p11.2del<\/jats:italic>mice, which is coincident with the development of aberrant cortical cytoarchitecture. The<jats:italic>16p11.2del<\/jats:italic>mice exhibit anxiety-like behaviors and impaired memory. Our findings provide evidence of ERK dysregulation, developmental abnormalities in neurogenesis, and behavioral impairment associated with the<jats:italic>16p11.2<\/jats:italic>chromosomal deletion.<\/jats:p>","DOI":"10.1523\/jneurosci.4864-13.2015","type":"journal-article","created":{"date-parts":[[2015,2,27]],"date-time":"2015-02-27T01:22:12Z","timestamp":1425000132000},"page":"3190-3200","source":"Crossref","is-referenced-by-count":193,"title":["The 16p11.2 Deletion Mouse Model of Autism Exhibits Altered Cortical Progenitor Proliferation and Brain Cytoarchitecture Linked to the ERK MAPK Pathway"],"prefix":"10.1523","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4227-657X","authenticated-orcid":false,"given":"Joanna","family":"Pucilowska","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Vithayathil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuel J.","family":"Tavares","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caitlin","family":"Kelly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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