Foxp1 regulation of neonatal vocalizations via cortical development
- Noriyoshi Usui1,2,3,
- Daniel J. Araujo1,7,
- Ashwinikumar Kulkarni1,
- Marissa Co1,
- Jacob Ellegood4,
- Matthew Harper1,
- Kazuya Toriumi1,5,
- Jason P. Lerch4,6 and
- Genevieve Konopka1
- 1Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
- 2Division of Development of Mental Functions, Research Center for Child Mental Development, University of Fukui, Fukui 910-1193, Japan;
- 3Division of Developmental Higher Brain Functions, Department of Child Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University, and University of Fukui, Osaka 565-0871, Japan;
- 4Mouse Imaging Centre (MICe), Hospital for Sick Children, Toronto, Ontario M5S 1A1, Canada;
- 5Project for Schizophrenia Research, Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan;
- 6Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5S 1A1, Canada
- Corresponding author: genevieve.konopka{at}utsouthwestern.edu
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.
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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.305037.117.
- Received July 19, 2017.
- Accepted October 25, 2017.
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