Protocadherins mediate dendritic self-avoidance in the mammalian nervous system

Area of Science:

• Neuroscience
• Developmental Biology
• Molecular Biology

Background:

• Neuronal dendritic arborizations are patterned by self-avoidance, where branches from the same neuron repel each other.
• Self-avoidance ensures complete coverage of a neuron's territory, minimizing gaps and overlaps.
• Some neurons that exhibit self-avoidance can interact with other neurons of the same subtype, suggesting self/non-self discrimination.

Purpose of the Study:

• To investigate the role of clustered protocadherins (Pcdhs) in dendritic self-avoidance and self/non-self discrimination.
• To elucidate the molecular mechanisms by which Pcdhs regulate neuronal wiring.

Main Methods:

• Genetic analysis of clustered protocadherin gamma (Pcdhg) genes in mouse retinal starburst amacrine cells (SACs) and cerebellar Purkinje cells.
• Functional studies involving gene deletion and isoform replacement to assess the impact on dendritic self-avoidance.
• Investigation of cell-autonomous functions of Pcdhg proteins during neuronal development.

Main Results:

• Deletion of Pcdhg genes disrupted dendritic self-avoidance in SACs and Purkinje cells.
• Pcdhg proteins act cell-autonomously; replacing 22 Pcdhg proteins with a single isoform restored self-avoidance.
• Expressing a single Pcdhg isoform in all SACs reduced interactions between dendrites of neighboring SACs (heteroneuronal interactions).

Conclusions:

• Homophilic Pcdhg interactions between sibling neurites (isoneuronal interactions) generate repulsive signals, leading to dendritic self-avoidance.
• Self/non-self discrimination is achieved because heteroneuronal interactions are permitted unless dendrites share a matched set of Pcdhg proteins.
• Vertebrate Pcdhs and insect Dscam1 employ similar strategies for neuronal self-avoidance and self/non-self discrimination, despite lacking sequence homology.