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Evolutionarily Dynamic Alternative Splicing of GPR56 Regulates Regional Cerebral Cortical Patterning

Lookup NU author(s): Dr Steven LisgoORCiD, Lynne Overman


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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.

Publication metadata

Author(s): Bae BI, Tietjen I, Atabay KD, Evrony GD, Johnson MB, Asare E, Wang PP, Murayama AY, Im K, Lisgo SN, Overman L, Sestan N, Chang BS, Barkovich AJ, Grant PE, Topcu M, Politsky J, Okano H, Piao XH, Walsh CA

Publication type: Article

Publication status: Published

Journal: Science

Year: 2014

Volume: 343

Issue: 6172

Pages: 764-768

Print publication date: 14/02/2014

Acceptance date: 17/12/2013

ISSN (print): 0036-8075

ISSN (electronic): 1095-9203

Publisher: American Association for the Advancement of Science


DOI: 10.1126/science.1244392


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Funder referenceFunder name
Ministry of Education, Culture, Sports, Science and Technology (MEXT) Japan
Paul G. Allen Family Foundation
Strategic Research Program for Brain Sciences
Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program)
2R01NS035129National Institute of Neurological Disorders and Stroke, NIH
G0700089Medical Research Council
HHSN275200900011CNational Institute of Child Health and Human Development, NIH, Brain and Tissue Bank at the University of Maryland
GR082557Wellcome Trust Human Developmental Biology Resource
NO1-HD-9-0011National Institute of Child Health and Human Development, NIH, Brain and Tissue Bank at the University of Maryland
U01MH081896National Institute of Mental Health, NIH