{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T19:20:59Z","timestamp":1788981659317,"version":"build-2803163510"},"posted":{"date-parts":[[2025,5,13]]},"group-title":"Neuroscience","reference-count":84,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T00:00:00Z","timestamp":1747094400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"funder":[{"name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","award":["R01 HD042182"],"award-info":[{"award-number":["R01 HD042182"]}]},{"name":"Seale Innovation Fund"},{"name":"Red Gates Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,8,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  The developmental origin of Layer 2\/3 projection neuron (PN) pathology in the frontal association cortex due to heterozygous 22q11 gene deletion\u2014the genetic foundation of elevated risk for schizophrenia and related psychiatric disorders in 22q11.2 Deletion Syndrome (22q11DS)\u2014reflects cell state-dependent, temporally restricted vulnerability of transcriptionally diverse subsets of intermediate progenitors and neuroblasts. The molecular and cell biological consequences of these evanescent state-dependent changes include divergent proliferative capacity of the most highly proliferative progenitors, enhanced neurogenic gene expression, altered DNA methylation, and increased numbers of immediate neuroblast progeny at peak neurogenesis in fetal frontal cortex of the\n                  <jats:italic>LgDel<\/jats:italic>\n                  22q11DS mouse model. These altered cell states prefigure a post-natal cohort of upper layer PNs generated at the peak of Layer 2\/3 PN genesis\u2014not before or after\u2014whose frequencies are significantly diminished and molecular identities are substantially divergent in medial frontal association, but not primary somatosensory or visual cortices. Thus, frontal association cortices in 22q11DS and schizophrenia more broadly may be pathogenic targets due to vulnerabilities of expanded, highly proliferative, transcriptionally dynamic populations of intermediate progenitors that increase L2\/3 PN frequency to enhance cortico-cortical connectivity.\n                <\/jats:p>","DOI":"10.1101\/2025.05.12.653556","type":"posted-content","created":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T05:05:27Z","timestamp":1747112727000},"source":"Crossref","is-referenced-by-count":2,"title":["Transient disruption of progenitor states and layer 2\/3 projection neuron generation in frontal association cortex due to 22q11.2 gene deletion"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7424-6386","authenticated-orcid":false,"given":"Shah","family":"Rukh","sequence":"first","affiliation":[{"name":"Center for Neurobiology Research, The Fralin Biomedical Research Institute at Virginia Tech-Carilion School of Medicine, 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