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Evolutionarily Dynamic Alternative Splicing of GPR56 Regulates Regional Cerebral Cortical Patterning

Byoung-Il Bae, Ian Tietjen, Kutay D. Atabay, Gilad D. Evrony, Matthew B. Johnson, Ebenezer Asare, Peter P. Wang, Ayako Y. Murayama, Kiho Im, Steven N. Lisgo, Lynne Overman, Nenad Šestan, Bernard S. Chang, A. James Barkovich, P. Ellen Grant, Meral Topçu, Jeffrey Politsky, Hideyuki Okano, Xianhua Piao, and Christopher A. Walsh [email protected]
Science • 14 Feb 2014 • Vol 343, Issue 6172 • pp. 764-768 • DOI: 10.1126/science.1244392
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Fine-Tuning Brain Gyrations

A handful of patients who suffer from seizures and mild intellectual disability have now led the way to insights about how one piece of regulatory DNA controls development of a section of the human cortex. Imaging the brains of these patients, Bae et al. (p. 764; see the Perspective by Rash and Rakic) observed malformations on the surface folds in a brain region that includes “Broca's area,” the main region underlying language. The three affected families shared a 15–base pair deletion in the regulatory region of a gene, GPR56, which encodes a G protein–coupled receptor required for normal cortical development that is expressed in cortical progenitor cells.

Abstract

The human neocortex has numerous specialized functional areas whose formation is poorly understood. Here, we describe a 15–base pair deletion mutation in a regulatory element of GPR56 that selectively disrupts human cortex surrounding the Sylvian fissure bilaterally including “Broca’s area,” the primary language area, by disrupting regional GPR56 expression and blocking RFX transcription factor binding. GPR56 encodes a heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptor required for normal cortical development and is expressed in cortical progenitor cells. GPR56 expression levels regulate progenitor proliferation. GPR56 splice forms are highly variable between mice and humans, and the regulatory element of gyrencephalic mammals directs restricted lateral cortical expression. Our data reveal a mechanism by which control of GPR56 expression pattern by multiple alternative promoters can influence stem cell proliferation, gyral patterning, and, potentially, neocortex evolution.
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Supplementary Material

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Materials and Methods
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Figs. S1 to S7
Tables S1 and S2
Movies S1 to S2
References (25–40)

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Science
Volume 343 | Issue 6172
14 February 2014

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Copyright © 2014, American Association for the Advancement of Science.

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Received: 7 August 2013
Accepted: 17 December 2013
Published in print: 14 February 2014

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Acknowledgments

Research performed on samples of human origin was conducted according to protocols approved by participating institutions, including Boston Children’s Hospital and Beth Israel Deaconess Medical Center. The human embryonic and fetal material was provided by the Joint Medical Research Council (grant no. G0700089)–Wellcome Trust (grant no. GR082557) Human Developmental Biology Resource (www.hdbr.org) and the National Institute of Child Health and Human Development, NIH, Brain and Tissue Bank at the University of Maryland (contract no. HHSN275200900011C, reference no. NO1-HD-9-0011). Gpr56 knockout mice are from Genentech. This work was supported by the Strategic Research Program for Brain Sciences and from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) Japan (H.O.); Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program) (H.O.); U01MH081896 from National Institute of Mental Health, NIH (N.S.); 2R01NS035129 from National Institute of Neurological Disorders and Stroke, NIH (C.A.W.); and The Paul G. Allen Family Foundation (C.A.W.). Additional funding support listed in supplementary materials. C.A.W. is an investigator of the Howard Hughes Medical Institute. Gpr56 knockout mice are available from Genentech subject to a Material Transfer Agreement.

Authors

Affiliations

Byoung-Il Bae*
Division of Genetics and Genomics, Manton Center for Orphan Disease, and Howard Hughes Medical Institute, Boston Children’s Hospital, Broad Institute of MIT and Harvard, and Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA.
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Ian Tietjen*,†
Division of Genetics and Genomics, Manton Center for Orphan Disease, and Howard Hughes Medical Institute, Boston Children’s Hospital, Broad Institute of MIT and Harvard, and Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA.
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Kutay D. Atabay
Division of Genetics and Genomics, Manton Center for Orphan Disease, and Howard Hughes Medical Institute, Boston Children’s Hospital, Broad Institute of MIT and Harvard, and Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA.
View all articles by this author
Gilad D. Evrony
Division of Genetics and Genomics, Manton Center for Orphan Disease, and Howard Hughes Medical Institute, Boston Children’s Hospital, Broad Institute of MIT and Harvard, and Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA.
View all articles by this author
Matthew B. Johnson
Division of Genetics and Genomics, Manton Center for Orphan Disease, and Howard Hughes Medical Institute, Boston Children’s Hospital, Broad Institute of MIT and Harvard, and Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA.
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Ebenezer Asare
Division of Genetics and Genomics, Manton Center for Orphan Disease, and Howard Hughes Medical Institute, Boston Children’s Hospital, Broad Institute of MIT and Harvard, and Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA.
View all articles by this author
Peter P. Wang
Division of Genetics and Genomics, Manton Center for Orphan Disease, and Howard Hughes Medical Institute, Boston Children’s Hospital, Broad Institute of MIT and Harvard, and Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA.
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Ayako Y. Murayama
Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan.
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Kiho Im
Division of Newborn Medicine, Center for Fetal Neonatal Neuroimaging and Developmental Science, Department of Radiology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
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Steven N. Lisgo
The MRC-Wellcome Trust Human Developmental Biology Resource (HDBR), Newcastle, Institute of Genetic Medicine, International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK.
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Lynne Overman
The MRC-Wellcome Trust Human Developmental Biology Resource (HDBR), Newcastle, Institute of Genetic Medicine, International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK.
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Nenad Šestan
Department of Neurobiology and Kavli Institute of Neuroscience, Yale University School of Medicine, New Haven, CT 06520, USA.
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Bernard S. Chang
Beth Israel Deaconess Medical Center, Comprehensive Epilepsy Center, Boston, MA 02215, USA.
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A. James Barkovich
Departments of Radiology, Pediatrics, Neurology, and Neurological Surgery, University of California San Francisco, San Francisco, CA 94143, USA.
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P. Ellen Grant
Division of Newborn Medicine, Center for Fetal Neonatal Neuroimaging and Developmental Science, Department of Radiology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
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Meral Topçu
Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey.
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Jeffrey Politsky‡
Department of Neurology, Medical College of Georgia, Augusta, GA 30912, USA.
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Hideyuki Okano
Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan.
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Xianhua Piao
Division of Newborn Medicine, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115, USA.
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Christopher A. Walsh§ [email protected]
Division of Genetics and Genomics, Manton Center for Orphan Disease, and Howard Hughes Medical Institute, Boston Children’s Hospital, Broad Institute of MIT and Harvard, and Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA.
View all articles by this author

Notes

*
The authors contributed equally to this work.
†
Present address: Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
‡
Present address: Northeast Regional Epilepsy Group, Atlantic Neuroscience Institute Epilepsy Center, Summit, NJ 07901, USA.
§Corresponding author. E-mail: [email protected]

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