@article{e88a20e1cf7c43e59fd02b91b748cf9a,
title = "Foxp1 regulation of neonatal vocalizations via cortical development",
abstract = "The molecular mechanisms driving brain development at risk in autism spectrum disorders (ASDs) remain mostly unknown. Previous studies have implicated the transcription factor FOXP1 in both brain development and ASD pathophysiology. However, the specific molecular pathways both upstream of and downstream from FOXP1 are not fully understood. To elucidate the contribution of FOXP1-mediated signaling to brain development and, in particular, neocortical development, we generated forebrain-specific Foxp1 conditional knockout mice. We show that deletion of Foxp1 in the developing forebrain leads to impairments in neonatal vocalizations as well as neocortical cytoarchitectonic alterations via neuronal positioning and migration. Using a genomics approach, we identified the transcriptional networks regulated by Foxp1 in the developing neocortex and found that such networks are enriched for downstream targets involved in neurogenesis and neuronal migration. We also uncovered mechanistic insight into Foxp1 function by demonstrating that sumoylation of Foxp1 during embryonic brain development is necessary for mediating proper interactions between Foxp1 and the NuRD complex. Furthermore, we demonstrated that sumoylation of Foxp1 affects neuronal differentiation and migration in the developing neocortex. Together, these data provide critical mechanistic insights into the function of FOXP1 in the developing neocortex and may reveal molecular pathways at risk in ASD.",
keywords = "Autism, Behavior, Neocortex, Neurogenomics, Neuronal migration, Sumoylation",
author = "Noriyoshi Usui and Araujo, {Daniel J.} and Ashwinikumar Kulkarni and Marissa Co and Jacob Ellegood and Matthew Harper and Kazuya Toriumi and Lerch, {Jason P.} and Genevieve Konopka",
note = "Funding Information: We thank Dr. Haley O. Tucker for providing the Foxp1flox/flox mice, and the Neuroscience Microscopy Facility at University of Texas Southwestern for imaging support. N.U. is a Research Fellow of the Uehara Memorial Foundation. M.C. is a Predoctoral Fellow of the Autism Science Foundation. G.K. is a Jon Heighten Scholar in Autism Research at University of Texas Southwestern. This work was supported by the Japan Society for the Promotion of Science Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers (S2603 to N.U., K.T., and G.K.); a National Science Foundation Graduate Research Fellowship Program grant (2013162469 to D.J.A.); the Howard Hughes Medical Institute Med into Grad Initiative and the National Institutes of Health (NIH; TL1TR001104 and T32GM109776 to M.C.); the Ontario Brain Institute, Brain Canada, and the Canadian Institute for Health Research (to J.P.L.); and a grant from the Simons Foundation (SFARI 401220), a research grant from the March of Dimes Foundation (5-FY13-19), and grants from the NIH (DC014702 and MH102603) (to G.K.). N.U. and G.K. designed the study, analyzed the data, and wrote the paper. N.U., D.J.A., M.C., M.H., and K.T. performed experiments and analyses. A.K. performed bioinformatic analyses. J.E. and J.P.L. performed MRI analyses. G.K. supervised this study and provided intellectual guidance. All authors discussed the results and commented on the manuscript. Publisher Copyright: {\textcopyright} 2017 Usui et al.",
year = "2017",
month = oct,
day = "15",
doi = "10.1101/gad.305037.117",
language = "English (US)",
volume = "31",
pages = "2039--2055",
journal = "Genes and Development",
issn = "0890-9369",
publisher = "Cold Spring Harbor Laboratory Press",
number = "20",
}