Evolutionarily Dynamic Alternative Splicing of GPR56 Regulates Regional Cerebral Cortical Patterning

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Science  14 Feb 2014:
Vol. 343, Issue 6172, pp. 764-768
DOI: 10.1126/science.1244392

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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.

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.

  • * 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.

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