Evolutionarily dynamic alternative splicing of GPR56 regulates regional cerebral cortical patterning

Area of Science:

• Neuroscience
• Developmental Biology
• Genetics

Background:

• The formation of specialized functional areas in the human neocortex is not well understood.
• GPR56 (G protein-coupled receptor 56) is crucial for normal cortical development and is expressed in cortical progenitor cells.
• GPR56 expression levels influence progenitor cell proliferation.

Purpose of the Study:

• To investigate the role of a specific mutation in a GPR56 regulatory element on human cortical development.
• To understand how this mutation affects gene expression and transcription factor binding.
• To explore the implications for neocortex evolution.

Main Methods:

• Identified a 15-base pair deletion mutation in a GPR56 regulatory element.
• Analyzed the impact of the mutation on GPR56 expression in the human cortex.
• Investigated the disruption of RFX transcription factor binding.
• Compared GPR56 splice forms and regulatory elements between species.

Main Results:

• The mutation selectively disrupted the human cortex surrounding the Sylvian fissure, including Broca's area.
• This disruption was caused by altered regional GPR56 expression and blocked RFX transcription factor binding.
• GPR56 splice forms and regulatory elements show significant variation between mice and humans.
• The regulatory element in gyrencephalic mammals directs restricted lateral cortical expression.

Conclusions:

• Control of GPR56 expression patterns through alternative promoters influences stem cell proliferation and brain folding (gyral patterning).
• This mechanism may play a role in the evolution of the neocortex.
• The study reveals a molecular mechanism underlying regional neocortical development and evolution.