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Peer-reviewedCC BY-NC-NDNature

Competing programs shape cortical sensorimotor–association axis development

  • Jeremiah Tsyporin1
  • Menglei Zhang1
  • Cai Qi1
  • Ashlea Segal1,2
  • Xinyun Li1
  • Hyo‐Jin Kim1
  • Sang-Hun Choi1
  • Ivan Pavlović1
  • Sara Bandiera1
  • Thomas S. Finn3
  • Suel–Kee Kim1
  • Akemi Shibata1
26 more authors
  • Takumi Nakamura1
  • Kohei Onishi4
  • Ziqin Zhang5,6
  • Elijah Hammarlund1
  • Graham Su1
  • Nikkita Salla1
  • Joy Kachko1
  • Christi Hawley1
  • Shuiyu Li1
  • Daniel Z. Doyle1,7
  • Xueyan Peng8
  • Timothy Nottoli9
  • Nuria Ruiz-Reig10
  • Fadel Tissir11,10
  • Yasushi Nakagawa12
  • Erica L. Herzog8
  • Shaojie Ma13
  • Kevin T. Gobeske1
  • Kartik Pattabiraman1,2,7
  • Tomomi Shimogori4
  • Alvaro Duque1
  • Alex Fornito14,15
  • Hao Huang5,6
  • Mikihito Shibata1
  • Bin Chen3
  • Nenad Šestan16,17,18,19,20,21,22,23,24
24 affiliations
  1. 1Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA
  2. 2Wu Tsai Institute, Yale University, New Haven, CT, USA
  3. 3Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, CA, USA
  4. 4Laboratory for Molecular Mechanisms of Brain Development, Center for Brain Science, RIKEN, Wako, Japan
  5. 5Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA
  6. 6Department of Radiology, Children's Hospital of Philadelphia, Philadelphia, PA, USA
  7. 7Yale Child Study Center, Yale School of Medicine, New Haven, CT, USA
  8. 8Department of Medicine (Pulmonary Critical Care and Sleep), Yale School of Medicine, New Haven, CT, USA
  9. 9Yale Genome Editing Center, Yale School of Medicine, New Haven, CT, USA
  10. 10Laboratory of Developmental Neurobiology, Institute of Neuroscience, Université Catholique de Louvain, Brussels, Belgium
  11. 11College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar
  12. 12Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN, USA
  13. 13Institute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
  14. 14Monash Biomedical Imaging, Monash University, Melbourne, Victoria, Australia
  15. 15Turner Institute for Brain and Mental Health, School of Psychological Sciences, Monash University, Melbourne, Victoria, Australia
  16. 16Department of Comparative Medicine, Yale University, New Haven, CT, USA. [email protected]
  17. 17Department of Genetics, Yale University, New Haven, CT, USA. [email protected]
  18. 18Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA. [email protected]
  19. 19Department of Psychiatry, New Haven, CT, USA. [email protected]
  20. 20Kavli Institute for Neuroscience, Yale University, New Haven, CT, USA. [email protected]
  21. 21Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University, New Haven, CT, USA. [email protected]
  22. 22Wu Tsai Institute, Yale University, New Haven, CT, USA. [email protected]
  23. 23Yale Child Study Center, Yale School of Medicine, New Haven, CT, USA. [email protected]
  24. 24Yale Genome Editing Center, Yale School of Medicine, New Haven, CT, USA. [email protected]
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Abstract

The neocortex is organized along a dominant sensorimotor-to-association (S-A) axis, anchored by modality-specific primary sensorimotor areas at one end and transmodal association areas that form distributed networks supporting abstract cognition at the other. The developmental mechanisms shaping this axis remain elusive. Here, we present converging multispecies evidence supporting the Multinodal Induction-Exclusion in Network Development (MIND) model, in which S-A patterning is governed by competing processes of induction and exclusion, driven by opposing transcriptomically-defined identity programs emerging from different nodes. Key molecular and connectional features of association cortices arise through pericentral programs, originating around fronto-temporal poles and partially regulated by retinoic acid. They progress inward toward central territories of the naïve neocortex along fronto-temporally polarized trajectories. Central programs are induced through interactions between topographically separated first-order sensorimotor thalamocortical inputs and the neocortex, promoting the formation of primary areas while excluding pericentral programs. Influenced by SATB2 and ZBTB18, these evolutionarily conserved programs compete for the same territory and create spatial compartmentalization of axon guidance, cell-cell adhesion, retinoic acid signaling, synaptogenesis, Wnt signaling, and autism risk genes. Notably, PLXNC1 and SEMA7A exhibit anti-correlated expression and repulsive functions in shaping cortico-cortical connectivity along the S-A axis. These processes of induction and exclusion establish an S-A equilibrium and topography in which primary sensorimotor areas emerge as focal islands within the broader ocean of distributed associative networks. The MIND model provides a unifying framework for understanding experimental, evolutionary, and clinical phenomena, revealing induction and exclusion as antagonistic complementary principles shaping the S-A axis and processing hierarchies.

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Cite

BibTeXRIS
BibTeX
@article{tsyporin2026competing,
  title = {{Competing programs shape cortical sensorimotor–association axis development}},
  author = {Jeremiah Tsyporin and Menglei Zhang and Cai Qi and Ashlea Segal and Xinyun Li and Hyo‐Jin Kim and Sang-Hun Choi and Ivan Pavlović and Sara Bandiera and Thomas S. Finn and Suel–Kee Kim and Akemi Shibata and Takumi Nakamura and Kohei Onishi and Ziqin Zhang and Elijah Hammarlund and Graham Su and Nikkita Salla and Joy Kachko and Christi Hawley and Shuiyu Li and Daniel Z. Doyle and Xueyan Peng and Timothy Nottoli and Nuria Ruiz-Reig and Fadel Tissir and Yasushi Nakagawa and Erica L. Herzog and Shaojie Ma and Kevin T. Gobeske and Kartik Pattabiraman and Tomomi Shimogori and Alvaro Duque and Alex Fornito and Hao Huang and Mikihito Shibata and Bin Chen and Nenad Šestan},
  journal = {Nature},
  year = {2026},
  month = jul,
  doi = {10.1038/s41586-026-10699-x},
  url = {https://doi.org/10.1038/s41586-026-10699-x},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Competing programs shape cortical sensorimotor–association axis development
AU  - Jeremiah Tsyporin
AU  - Menglei Zhang
AU  - Cai Qi
AU  - Ashlea Segal
AU  - Xinyun Li
AU  - Hyo‐Jin Kim
AU  - Sang-Hun Choi
AU  - Ivan Pavlović
AU  - Sara Bandiera
AU  - Thomas S. Finn
AU  - Suel–Kee Kim
AU  - Akemi Shibata
AU  - Takumi Nakamura
AU  - Kohei Onishi
AU  - Ziqin Zhang
AU  - Elijah Hammarlund
AU  - Graham Su
AU  - Nikkita Salla
AU  - Joy Kachko
AU  - Christi Hawley
AU  - Shuiyu Li
AU  - Daniel Z. Doyle
AU  - Xueyan Peng
AU  - Timothy Nottoli
AU  - Nuria Ruiz-Reig
AU  - Fadel Tissir
AU  - Yasushi Nakagawa
AU  - Erica L. Herzog
AU  - Shaojie Ma
AU  - Kevin T. Gobeske
AU  - Kartik Pattabiraman
AU  - Tomomi Shimogori
AU  - Alvaro Duque
AU  - Alex Fornito
AU  - Hao Huang
AU  - Mikihito Shibata
AU  - Bin Chen
AU  - Nenad Šestan
PY  - 2026
DA  - 2026/07/01
JO  - Nature
DO  - 10.1038/s41586-026-10699-x
UR  - https://doi.org/10.1038/s41586-026-10699-x
AB  - The neocortex is organized along a dominant sensorimotor-to-association (S-A) axis, anchored by modality-specific primary sensorimotor areas at one end and transmodal association areas that form distributed networks supporting abstract cognition at the other. The developmental mechanisms shaping this axis remain elusive. Here, we present converging multispecies evidence supporting the Multinodal Induction-Exclusion in Network Development (MIND) model, in which S-A patterning is governed by competing processes of induction and exclusion, driven by opposing transcriptomically-defined identity programs emerging from different nodes. Key molecular and connectional features of association cortices arise through pericentral programs, originating around fronto-temporal poles and partially regulated by retinoic acid. They progress inward toward central territories of the naïve neocortex along fronto-temporally polarized trajectories. Central programs are induced through interactions between topographically separated first-order sensorimotor thalamocortical inputs and the neocortex, promoting the formation of primary areas while excluding pericentral programs. Influenced by SATB2 and ZBTB18, these evolutionarily conserved programs compete for the same territory and create spatial compartmentalization of axon guidance, cell-cell adhesion, retinoic acid signaling, synaptogenesis, Wnt signaling, and autism risk genes. Notably, PLXNC1 and SEMA7A exhibit anti-correlated expression and repulsive functions in shaping cortico-cortical connectivity along the S-A axis. These processes of induction and exclusion establish an S-A equilibrium and topography in which primary sensorimotor areas emerge as focal islands within the broader ocean of distributed associative networks. The MIND model provides a unifying framework for understanding experimental, evolutionary, and clinical phenomena, revealing induction and exclusion as antagonistic complementary principles shaping the S-A axis and processing hierarchies.
SN  - 0028-0836
SN  - 1476-4687
ER  -