Evolutionarily dynamic alternative splicing of GPR56 regulates regional cerebral cortical patterning

Science. 2014 Feb 14;343(6172):764-8. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing*
  • Animals
  • Base Sequence
  • Biological Evolution
  • Body Patterning / genetics*
  • Cats
  • Cell Proliferation
  • Cerebral Cortex / anatomy & histology
  • Cerebral Cortex / cytology
  • Cerebral Cortex / embryology*
  • Codon, Nonsense
  • Frontal Lobe / anatomy & histology
  • Frontal Lobe / cytology
  • Frontal Lobe / embryology
  • Genetic Variation
  • Haplotypes
  • Humans
  • Mice
  • Molecular Sequence Data
  • Neural Stem Cells / cytology
  • Neural Stem Cells / physiology*
  • Pedigree
  • Promoter Regions, Genetic / genetics
  • Receptors, G-Protein-Coupled / genetics*
  • Sequence Deletion

Substances

  • ADGRG1 protein, human
  • Codon, Nonsense
  • GPR56 protein, mouse
  • Receptors, G-Protein-Coupled