title: Evolutionarily dynamic alternative splicing of GPR56 regulates regional cerebral cortical patterning.
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.
authors: 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.
authors: Byoung-Il
authors: BI
authors: Bae
authors: Ian
authors: I
authors: Tietjen
authors: Kutay D
authors: KD
authors: Atabay
authors: Gilad D
authors: GD
authors: Evrony
authors: Matthew B
authors: MB
authors: Johnson
authors: Ebenezer
authors: E
authors: Asare
authors: Peter P
authors: PP
authors: Wang
authors: Ayako Y
authors: AY
authors: Murayama
authors: Kiho
authors: K
authors: Im
authors: Steven N
authors: SN
authors: Lisgo
authors: Lynne
authors: L
authors: Overman
authors: Nenad
authors: N
authors: Šestan
authors: Bernard S
authors: BS
authors: Chang
authors: A James
authors: AJ
authors: Barkovich
authors: P Ellen
authors: PE
authors: Grant
authors: Meral
authors: M
authors: Topçu
authors: Jeffrey
authors: J
authors: Politsky
authors: Hideyuki
authors: H
authors: Okano
authors: Xianhua
authors: X
authors: Piao
authors: Christopher A
authors: CA
authors: Walsh
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001483:Base Sequence; D005075:Biological Evolution; D019521:Body Patterning / Q000235:genetics*; D002415:Cats; D049109:Cell Proliferation; D002540:Cerebral Cortex / Q000033:anatomy & histology / Q000166:cytology / Q000196:embryology*; D018389:Codon, Nonsense; D005625:Frontal Lobe / Q000033:anatomy & histology / Q000166:cytology / Q000196:embryology; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D058953:Neural Stem Cells / Q000166:cytology / Q000502:physiology*; D010375:Pedigree; D011401:Promoter Regions, Genetic / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D017384:Sequence Deletion
chemical_list: D018389:Codon, Nonsense; D043562:Receptors, G-Protein-Coupled; C118925:ADGRG1 protein, human; C524781:Adgrg1 protein, mouse