@article {Pucilowska3190, author = {Joanna Pucilowska and Joseph Vithayathil and Emmanuel J. Tavares and Caitlin Kelly and J. Colleen Karlo and Gary E. Landreth}, title = {The 16p11.2 Deletion Mouse Model of Autism Exhibits Altered Cortical Progenitor Proliferation and Brain Cytoarchitecture Linked to the ERK MAPK Pathway}, volume = {35}, number = {7}, pages = {3190--3200}, year = {2015}, doi = {10.1523/JNEUROSCI.4864-13.2015}, publisher = {Society for Neuroscience}, abstract = {Autism spectrum disorders are complex, highly heritable neurodevelopmental disorders affecting \~{}1 in 100 children. Copy number variations of human chromosomal region 16p11.2 are genetically linked to 1\% of autism-related disorders. This interval contains the MAPK3 gene, which encodes the MAP kinase, ERK1. 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 16p11.2 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 p27Kip1 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 16p11.2del mice, which is coincident with the development of aberrant cortical cytoarchitecture. The 16p11.2del 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 16p11.2 chromosomal deletion.}, issn = {0270-6474}, URL = {https://www.jneurosci.org/content/35/7/3190}, eprint = {https://www.jneurosci.org/content/35/7/3190.full.pdf}, journal = {Journal of Neuroscience} }