Temporal controls over inter-areal cortical projection neuron fate diversity

Esther Klingler, Ugo Tomasello, Julien Prados, Justus M. Kebschull, Alessandro Contestabile, Gregorio L. Galiñanes, Sabine Fièvre, Antonio Santinha, Randall Platt, Daniel Huber, Alexandre Dayer, Camilla Bellone and Denis Jabaudon ()
Additional contact information
Esther Klingler: University of Geneva
Ugo Tomasello: University of Geneva
Julien Prados: Geneva University Hospital
Justus M. Kebschull: Cold Spring Harbor Laboratory, Cold Spring Harbor
Alessandro Contestabile: University of Geneva
Gregorio L. Galiñanes: University of Geneva
Sabine Fièvre: University of Geneva
Antonio Santinha: ETH Zurich
Randall Platt: ETH Zurich
Daniel Huber: University of Geneva
Alexandre Dayer: University of Geneva
Camilla Bellone: University of Geneva
Denis Jabaudon: University of Geneva

Nature, 2021, vol. 599, issue 7885, 453-457

Abstract: Abstract Interconnectivity between neocortical areas is critical for sensory integration and sensorimotor transformations1–6. These functions are mediated by heterogeneous inter-areal cortical projection neurons (ICPN), which send axon branches across cortical areas as well as to subcortical targets7–9. Although ICPN are anatomically diverse10–14, they are molecularly homogeneous15, and how the diversity of their anatomical and functional features emerge during development remains largely unknown. Here we address this question by linking the connectome and transcriptome in developing single ICPN of the mouse neocortex using a combination of multiplexed analysis of projections by sequencing16,17 (MAPseq, to identify single-neuron axonal projections) and single-cell RNA sequencing (to identify corresponding gene expression). Focusing on neurons of the primary somatosensory cortex (S1), we reveal a protracted unfolding of the molecular and functional differentiation of motor cortex-projecting ( $$\vec{{\rm{M}}}$$ M ⃗ ) ICPN compared with secondary somatosensory cortex-projecting ( $$\vec{{\rm{S}}2}$$ S 2 ⃗ ) ICPN. We identify SOX11 as a temporally differentially expressed transcription factor in $$\vec{{\rm{M}}}$$ M ⃗ versus $$\vec{{\rm{S}}2}$$ S 2 ⃗ ICPN. Postnatal manipulation of SOX11 expression in S1 impaired sensorimotor connectivity and disrupted selective exploratory behaviours in mice. Together, our results reveal that within a single cortical area, different subtypes of ICPN have distinct postnatal paces of molecular differentiation, which are subsequently reflected in distinct circuit connectivities and functions. Dynamic differences in the expression levels of a largely generic set of genes, rather than fundamental differences in the identity of developmental genetic programs, may thus account for the emergence of intra-type diversity in cortical neurons.

Date: 2021
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DOI: 10.1038/s41586-021-04048-3

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