Capicua Refines Mossy Fiber-CA3 Axon Targeting in the Late Postnatal Hippocampus

Area of Science:

• Neuroscience
• Developmental Biology
• Molecular Biology

Background:

• Proper brain wiring requires precise axonal projections for neural circuit assembly.
• The mossy fiber (MF)-CA3 pathway in the hippocampus demonstrates lamina-specific connectivity.
• Mechanisms guiding MF targeting to continuously generated granule neurons are not fully understood.

Purpose of the Study:

• Investigate the role of the neurodevelopmental disorder-associated protein capicua (CIC) in MF-CA3 pathway targeting.
• Determine the cell-type specificity of CIC's function in MF targeting.
• Elucidate the molecular mechanisms underlying CIC-dependent MF connectivity.

Main Methods:

• Utilized mouse models with targeted deletion of the capicua (CIC) gene.
• Performed histological analysis of hippocampal circuitry.
• Employed single-nucleus transcriptomics and trajectory analysis.

Main Results:

• Deletion of CIC in dentate gyrus granule neurons leads to abnormal MF targeting after the second postnatal week.
• This miswiring persists into adulthood and is not observed in CA3 pyramidal neurons.
• CIC loss results in the absence of a mature granule neuron subtype and dysregulated axon guidance gene expression.

Conclusions:

• Capicua (CIC) plays a previously unrecognized role in postnatal hippocampus development.
• CIC regulates lamina-specific MF connectivity by influencing granule neuron maturation and axon guidance gene expression.
• Findings provide insights into the molecular basis of neural circuit assembly and potential mechanisms underlying neurodevelopmental disorders.