Molecular programs guiding arealization of descending cortical pathways

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Philipp Abe - , Institute of Anatomy, University of Geneva (Author)
  • Adrien Lavalley - , University of Geneva, Geneva University Hospitals (Author)
  • Ilaria Morassut - , University of Geneva (Author)
  • Antonio J. Santinha - , ETH Zurich (Author)
  • Sergi Roig-Puiggros - , University of Geneva (Author)
  • Awais Javed - , University of Geneva (Author)
  • Esther Klingler - , University of Geneva, KU Leuven (Author)
  • Natalia Baumann - , University of Geneva (Author)
  • Julien Prados - , University of Geneva (Author)
  • Randall J. Platt - , ETH Zurich, University of Basel (Author)
  • Denis Jabaudon - , University of Geneva, Geneva University Hospitals, Université Paris Cité (Author)

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) Nprs1- 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.

Details

Original languageEnglish
Pages (from-to)644-651
Number of pages8
JournalNature
Volume634
Issue number8034
Publication statusPublished - 17 Oct 2024
Peer-reviewedYes

External IDs

Scopus 85203523763
PubMed 39261725

Keywords