Molecular programs guiding arealization of descending cortical pathways

• 成果类型: Article
• 署名作者: Abe, Philipp; Lavalley, Adrien; Morassut, Ilaria; Santinha, Antonio J.; Roig-Puiggros, Sergi; Javed, Awais; Klingler, Esther; Baumann, Natalia; Prados, Julien; Platt, Randall J.; Jabaudon, Denis
• 署名单位: University of Geneva; Technische Universitat Dresden; Carl Gustav Carus University Hospital; University of Geneva; Swiss Federal Institutes of Technology Domain; ETH Zurich; Flanders Institute for Biotechnology (VIB); University of Geneva; University of Basel; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Cite
• 刊物名称: Nature
• ISSN/ISSBN: 0028-6807
• DOI: 10.1038/s41586-024-07895-y
• 发表日期: 2024-10-17
• 关键词: transcriptomic cell-types; subtype-specific genes; postnatal-development; corticospinal tract; axon; projection; neurons; connectivity; expression; cortex

摘要

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. Using cross-areal mapping of axonal projections in the mouse neocortex, we identify the subtype-specific developmental dynamics of extratelencephalic neurons and show the functional transcriptional programs driving extratelencephalic neuron diversity.