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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.

SUBMITTER: Bae BI

PROVIDER: S-EPMC4480613 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Evolutionarily dynamic alternative splicing of GPR56 regulates regional cerebral cortical patterning.

Bae Byoung-Il BI Tietjen Ian I Atabay Kutay D KD Evrony Gilad D GD Johnson Matthew B MB Asare Ebenezer E Wang Peter P PP Murayama Ayako Y AY Im Kiho K Lisgo Steven N SN Overman Lynne L Šestan Nenad N Chang Bernard S BS Barkovich A James AJ Grant P Ellen PE Topçu Meral M Politsky Jeffrey J Okano Hideyuki H Piao Xianhua X Walsh Christopher A CA

Science (New York, N.Y.) 20140201 6172

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 recepto ...[more]

PMID: 24531968

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Project description:Despite the well-established role of the frontal and posterior peri-sylvian cortices in many facets of human-cognitive specializations, including language, little is known about the developmental patterning of these regions in human brain. We performed a genome-wide analysis of human cerebral patterning during mid-gestation, a critical epoch in cortical regionalization. A total of 345 genes were identified as differentially expressed (DE) between superior temporal gyrus (STG) and the remaining cerebral cortex (CTX). GO categories representing transcription factors were enriched in STG, while cell-adhesion and extracellular matrix molecules, were enriched in the other cortical regions. Q-PCR or in situ hybridization were performed to validate differential expression in a subset of 32 genes, most of which were confirmed. LIM domain binding 1 (LDB1), which we show to be enriched in the STG, is a recently identified interactor of LIM domain only 4 (LMO4), a gene known to be involved in the asymmetric pattering of the peri-sylvian region in the developing human brain. Protocadherin 17 (PCDH17), a neuronal cell adhesion molecule, was highly enriched in focal regions of the human prefrontal cortex. Contactin Associated Protein-Like 2 (CNTNAP2), in which mutations are known to cause autism, epilepsy and language delay, showed a remarkable pattern of anterior enriched expression in cortical regions important for human higher cognition. Importantly, a similar pattern was not observed in the mouse or rat. These data highlight the importance of expression analysis of human brain and the utility of cross-species comparisons of gene expression. Genes identified here provide a foundation for understanding molecular aspects of human-cognitive specializations and disorders that disrupt them. Experiment Overall Design: Fresh frozen human mid-gestation brains were obtained from the NICHD Brain and Tissue Bank for Developmental Disorders (University of Maryland, Baltimore, MD). After separation of the two hemispheres, tissue from STG was extracted. RNA from STG and remaining CTX was hybridized on both Agilent G4110A arrays (n=8) and Affymetrix HGU133A arrays (n=17).

Dataset Information

Evolutionarily dynamic alternative splicing of GPR56 regulates regional cerebral cortical patterning.

Publications

Evolutionarily dynamic alternative splicing of GPR56 regulates regional cerebral cortical patterning.

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