Protocadherin γC4 regulates neuronal survival and dendritic self-avoidance

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Protocadherin gamma C4 (γC4) is one of 22 isoforms in the Pcdh-γ gene cluster.
• Mutations in γC4 are linked to human neurodevelopmental syndromes, including microcephaly, seizures, and intellectual disability.

Purpose of the Study:

• To establish and characterize a γC4 mutant mouse model for studying associated neurodevelopmental disorders.
• To investigate the specific role of γC4 within the Pcdh-γ gene cluster using a novel genome-editing strategy.

Main Methods:

• Generation of a γC4 mutant mouse model exhibiting key features of the human syndrome.
• Utilized DOMINO (Double Mutation-Induced Open Reading Frame Switch), a two-step CRISPR/Cas9 genome-editing strategy.
• Generated γC4fl-only mice to isolate the function of full-length γC4.

Main Results:

• The γC4 mutant mouse model displayed motor dysfunction, seizures, reduced brain size, and increased embryonic neuronal apoptosis.
• γC4fl-only mice were viable and fertile, unlike Pcdh-γ cluster-deficient mice.
• The γC4 constant region (γCR) was found to regulate Purkinje cell dendritic architecture and self-avoidance.

Conclusions:

• γC4 is essential for neuronal survival and proper dendritic patterning.
• γC4 plays a principal functional role within the Pcdh-γ gene cluster.
• The γC4 mutant mouse model serves as a valuable tool for understanding γC4-related neurodevelopmental disorders.