2. Academic Validation
  3. Evolutionarily dynamic alternative splicing of GPR56 regulates regional cerebral cortical patterning

Evolutionarily dynamic alternative splicing of GPR56 regulates regional cerebral cortical patterning

  • Science. 2014 Feb 14;343(6172):764-8. doi: 10.1126/science.1244392.
Byoung-Il Bae 1,  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,  Christopher A Walsh
Affiliations

Affiliation

  • 1 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.
PMID: 24531968 DOI: 10.1126/science.1244392
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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