Temporal controls over inter-areal cortical projection neuron fate diversity

Area of Science:

• Neuroscience
• Developmental Biology
• Molecular Biology

Background:

• Neocortical interconnectivity is vital for sensory integration and sensorimotor transformations.
• Inter-areal cortical projection neurons (ICPN) mediate these functions but their developmental origins are unclear.
• Existing research shows anatomical diversity but molecular homogeneity in ICPN.

Purpose of the Study:

• To investigate the developmental emergence of anatomical and functional diversity in single ICPN.
• To link the connectome and transcriptome of developing ICPN in the mouse neocortex.
• To identify molecular mechanisms driving ICPN subtype differentiation.

Main Methods:

• Combined multiplexed analysis of projections by sequencing (MAPseq) and single-cell RNA sequencing.
• Analyzed single ICPN from the primary somatosensory cortex (S1) of developing mice.
• Investigated the role of SOX11 by postnatal manipulation of its expression.

Main Results:

• Revealed distinct postnatal molecular and functional differentiation paces for motor cortex-projecting vs. secondary somatosensory cortex-projecting ICPN.
• Identified SOX11 as a key transcription factor differentially expressed between these ICPN subtypes.
• Demonstrated that SOX11 manipulation in S1 impacts sensorimotor connectivity and exploratory behaviors.

Conclusions:

• Different ICPN subtypes exhibit distinct postnatal molecular differentiation rates, influencing circuit connectivity and function.
• Temporal gene expression dynamics, particularly SOX11, contribute to intra-type diversity in cortical neurons.
• Developmental pace, rather than distinct genetic programs, may underlie ICPN diversity.