{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Neuroscience, Yale School of Medicine, New Haven, CT USA",
    "Yale Genome Editing Center, Yale School of Medicine, New Haven, CT USA",
    "Institute of Developmental and Regenerative Medicine, Department of Paediatrics, University of Oxford, Oxford, UK",
    "New York Genome Center, New York, NY USA",
    "Yale Child Study Center, Yale School of Medicine, New Haven, CT USA",
    "Wu Tsai Institute, Yale University, New Haven, CT USA",
    "Department of Comparative Medicine, Yale School of Medicine, New Haven, CT USA",
    "Department of Genetics, Yale School of Medicine, New Haven, CT USA",
    "Department of Neurosurgery, Yale School of Medicine, New Haven, CT USA",
    "Department of Psychiatry, Yale School of Medicine, New Haven, CT USA"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 18,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Lin Yang"
    },
    {
      "affs": [
        0
      ],
      "name": "Mikihito Shibata"
    },
    {
      "affs": [
        0
      ],
      "name": "Saejeong Park"
    },
    {
      "affs": [
        0
      ],
      "name": "Yuting Liu"
    },
    {
      "affs": [
        0
      ],
      "name": "Iva Salamon"
    },
    {
      "affs": [
        0
      ],
      "name": "Jia Liu",
      "orcid": "0000-0001-8028-4506"
    },
    {
      "affs": [
        0
      ],
      "name": "Suel-Kee Kim",
      "orcid": "0000-0003-0240-9304"
    },
    {
      "affs": [
        0
      ],
      "name": "Akemi Shibata",
      "orcid": "0009-0006-6761-691X"
    },
    {
      "affs": [
        0
      ],
      "name": "Ashley Deveau-French",
      "orcid": "0009-0006-2655-8602"
    },
    {
      "affs": [
        0
      ],
      "name": "Xoel Mato Blanco",
      "orcid": "0000-0003-2155-9922"
    },
    {
      "affs": [
        1
      ],
      "name": "Suxia Bai"
    },
    {
      "affs": [
        1
      ],
      "name": "Timothy Nottoli",
      "orcid": "0000-0002-2218-5590"
    },
    {
      "affs": [
        1
      ],
      "name": "Xiaojun Xing"
    },
    {
      "affs": [
        2
      ],
      "name": "Narjes Rohani",
      "orcid": "0000-0003-4441-9359"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Stephan J. Sanders",
      "orcid": "0000-0001-9112-5148"
    },
    {
      "affs": [
        0
      ],
      "name": "Rothem Kovner"
    },
    {
      "affs": [
        0,
        4,
        5
      ],
      "name": "Kartik Pattabiraman"
    },
    {
      "affs": [
        0,
        1,
        4,
        5,
        6,
        7,
        8,
        9
      ],
      "name": "Nenad Sestan",
      "orcid": "0000-0003-0966-9619"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/d6w31jvmwkkzz.bib",
  "cited_by": 4,
  "doi": "10.1038/s41586-026-11014-4",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13736201/",
  "id": "d6w31jvmwkkzz",
  "issns": [
    "0028-0836",
    "1476-4687"
  ],
  "landing_url": "https://doi.org/10.1038/s41586-026-11014-4",
  "language": "en",
  "licence": "CC-BY-NC-ND-4.0",
  "licence_label": "CC BY-NC-ND 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Article"
    ],
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      "openalex",
      "2806|Neurogenesis and neuroplasticity mechanisms"
    ]
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  "openalex": "W7213394018",
  "pdf_url": null,
  "pmcid": "PMC13736201",
  "pmid": "42749810",
  "published": "2026-09-16",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/d6w31jvmwkkzz.ris",
  "sources": [
    {
      "first_seen": "2026-11-09T12:21:43Z",
      "native_id": "PMC13736201",
      "source": "pmc",
      "url": "https://doi.org/10.1038/s41586-026-11014-4"
    }
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  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2806|Neurogenesis and neuroplasticity mechanisms",
      "subfield": "neuroscience"
    }
  ],
  "title": "A retinoic acid autoregulatory loop governing prefrontal–motor arealization",
  "title_text": "A retinoic acid autoregulatory loop governing prefrontal–motor arealization",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T12:21:43Z",
  "url": "https://research.draconitic.com/paper/d6w31jvmwkkzz",
  "venue": "Nature",
  "versions": []
}