Molecular programs guiding arealization of descending cortical pathways

Philipp Abe, Adrien Lavalley, Ilaria Morassut, Antonio J. Santinha, Sergi Roig-Puiggros, Awais Javed, Esther Klingler, Natalia Baumann, Julien Prados, Randall J. Platt and Denis Jabaudon ()
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Philipp Abe: University of Geneva
Adrien Lavalley: University of Geneva
Ilaria Morassut: University of Geneva
Antonio J. Santinha: ETH Zurich
Sergi Roig-Puiggros: University of Geneva
Awais Javed: University of Geneva
Esther Klingler: University of Geneva
Natalia Baumann: University of Geneva
Julien Prados: University of Geneva
Randall J. Platt: ETH Zurich
Denis Jabaudon: University of Geneva

Nature, 2024, vol. 634, issue 8034, 644-651

Abstract: Abstract Layer 5 extratelencephalic (ET) neurons are present across neocortical areas and send axons to multiple subcortical targets1–6. Two cardinal subtypes exist7,8: (1) Slco2a1-expressing neurons (ETdist), which predominate in the motor cortex and project distally to the pons, medulla and spinal cord; and (2) Npsr1- or Hpgd-expressing neurons (ETprox), which predominate in the visual cortex and project more proximally to the pons and thalamus. An understanding of how area-specific ETdist and ETprox emerge during development is important because they are critical for fine motor skills and are susceptible to spinal cord injury and amyotrophic lateral sclerosis9–12. Here, using cross-areal mapping of axonal projections in the mouse neocortex, we identify the subtype-specific developmental dynamics of ET neurons. Whereas subsets of ETprox emerge by pruning of ETdist axons, others emerge de novo. We outline corresponding subtype-specific developmental transcriptional programs using single-nucleus sequencing. Leveraging these findings, we use postnatal in vivo knockdown of subtype-specific transcription factors to reprogram ET neuron connectivity towards more proximal targets. Together, these results show the functional transcriptional programs driving ET neuron diversity and uncover cell subtype-specific gene regulatory networks that can be manipulated to direct target specificity in motor corticofugal pathways.

Date: 2024
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DOI: 10.1038/s41586-024-07895-y

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