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Peer-reviewedCC BY-NC-ND 4.0Nature

A retinoic acid autoregulatory loop governing prefrontal–motor arealization

  • Lin Yang1
  • Mikihito Shibata1
  • Saejeong Park1
  • Yuting Liu1
  • Iva Salamon1
  • Jia Liu1
  • Suel-Kee Kim1
  • Akemi Shibata1
  • Ashley Deveau-French1
  • Xoel Mato Blanco1
  • Suxia Bai2
  • Timothy Nottoli2
6 more authors
  • Xiaojun Xing2
  • Narjes Rohani3
  • Stephan J. Sanders3,4
  • Rothem Kovner1
  • Kartik Pattabiraman1,5,6
  • Nenad Sestan1,2,5,6,7,8,9,10
10 affiliations
  1. 1Department of Neuroscience, Yale School of Medicine, New Haven, CT USA
  2. 2Yale Genome Editing Center, Yale School of Medicine, New Haven, CT USA
  3. 3Institute of Developmental and Regenerative Medicine, Department of Paediatrics, University of Oxford, Oxford, UK
  4. 4New York Genome Center, New York, NY USA
  5. 5Yale Child Study Center, Yale School of Medicine, New Haven, CT USA
  6. 6Wu Tsai Institute, Yale University, New Haven, CT USA
  7. 7Department of Comparative Medicine, Yale School of Medicine, New Haven, CT USA
  8. 8Department of Genetics, Yale School of Medicine, New Haven, CT USA
  9. 9Department of Neurosurgery, Yale School of Medicine, New Haven, CT USA
  10. 10Department of Psychiatry, Yale School of Medicine, New Haven, CT USA
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Abstract

The frontal lobe comprises the prefrontal association cortex (PFC), which supports complex cognition and goal-directed behaviour, and the motor cortex (MC), which executes movement1–14. The establishment of distinct regional identities and connections along the sensorimotor-to-association axis provides a fundamental scaffold for cortical areal organization and function15–19. Retinoic acid (RA) signalling has emerged as a key regulator of PFC development19–26. However, the mechanisms that spatially confine RA signalling within the developing PFC, and the downstream RA-responsive gene networks, remain poorly understood. Here we define an RA-associated gene regulatory network in the developing human PFC and identify MEIS2, which encodes a transcription factor linked to intellectual disability and autism spectrum disorder, as a key hub of this network. Conditional deletion of Meis2 in postmitotic cortical excitatory neurons in mice results in a partial respecification of prospective prefrontal association territories towards motor-like molecular and connectivity features, highlighting a critical role of postmitotic neurons in establishing and maintaining cortical areal identities. Concomitant with Meis2 loss, the population of excitatory neurons expressing the RA-synthesizing enzyme ALDH1A3, and consequently RA signalling itself, is substantially reduced in the developing medial PFC (mPFC). These findings reveal a conserved autoregulatory loop, RA → MEIS2 → ALDH1A3 → RA, that reinforces a PFC-enriched RA gradient and organizes the MC–PFC axis. Together, our findings reveal a postmitotic mechanism by which specific features of neuronal identity reinforce RA signalling to define key features of prefrontal and motor cortical territories, linking a classic morphogen to transcriptional identity, neural circuit formation and function, and potentially to neuropsychiatric disorders.

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Cite

BibTeXRIS
BibTeX
@article{yang2026retinoic,
  title = {{A retinoic acid autoregulatory loop governing prefrontal–motor arealization}},
  author = {Lin Yang and Mikihito Shibata and Saejeong Park and Yuting Liu and Iva Salamon and Jia Liu and Suel-Kee Kim and Akemi Shibata and Ashley Deveau-French and Xoel Mato Blanco and Suxia Bai and Timothy Nottoli and Xiaojun Xing and Narjes Rohani and Stephan J. Sanders and Rothem Kovner and Kartik Pattabiraman and Nenad Sestan},
  journal = {Nature},
  year = {2026},
  month = sep,
  doi = {10.1038/s41586-026-11014-4},
  url = {https://doi.org/10.1038/s41586-026-11014-4},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - A retinoic acid autoregulatory loop governing prefrontal–motor arealization
AU  - Lin Yang
AU  - Mikihito Shibata
AU  - Saejeong Park
AU  - Yuting Liu
AU  - Iva Salamon
AU  - Jia Liu
AU  - Suel-Kee Kim
AU  - Akemi Shibata
AU  - Ashley Deveau-French
AU  - Xoel Mato Blanco
AU  - Suxia Bai
AU  - Timothy Nottoli
AU  - Xiaojun Xing
AU  - Narjes Rohani
AU  - Stephan J. Sanders
AU  - Rothem Kovner
AU  - Kartik Pattabiraman
AU  - Nenad Sestan
PY  - 2026
DA  - 2026/09/16
JO  - Nature
DO  - 10.1038/s41586-026-11014-4
UR  - https://doi.org/10.1038/s41586-026-11014-4
AB  - The frontal lobe comprises the prefrontal association cortex (PFC), which supports complex cognition and goal-directed behaviour, and the motor cortex (MC), which executes movement1–14. The establishment of distinct regional identities and connections along the sensorimotor-to-association axis provides a fundamental scaffold for cortical areal organization and function15–19. Retinoic acid (RA) signalling has emerged as a key regulator of PFC development19–26. However, the mechanisms that spatially confine RA signalling within the developing PFC, and the downstream RA-responsive gene networks, remain poorly understood. Here we define an RA-associated gene regulatory network in the developing human PFC and identify MEIS2, which encodes a transcription factor linked to intellectual disability and autism spectrum disorder, as a key hub of this network. Conditional deletion of Meis2 in postmitotic cortical excitatory neurons in mice results in a partial respecification of prospective prefrontal association territories towards motor-like molecular and connectivity features, highlighting a critical role of postmitotic neurons in establishing and maintaining cortical areal identities. Concomitant with Meis2 loss, the population of excitatory neurons expressing the RA-synthesizing enzyme ALDH1A3, and consequently RA signalling itself, is substantially reduced in the developing medial PFC (mPFC). These findings reveal a conserved autoregulatory loop, RA → MEIS2 → ALDH1A3 → RA, that reinforces a PFC-enriched RA gradient and organizes the MC–PFC axis. Together, our findings reveal a postmitotic mechanism by which specific features of neuronal identity reinforce RA signalling to define key features of prefrontal and motor cortical territories, linking a classic morphogen to transcriptional identity, neural circuit formation and function, and potentially to neuropsychiatric disorders.
SN  - 0028-0836
SN  - 1476-4687
ER  -