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Using a gyrencephalic CH pig model, we observed cerebral atrophy and cortical hypogyrification, mirroring key neuropathological features of CH patients. Histological analyses revealed that glial cells were more prominently affected than cortical neurons, with reduced differentiated astrocytic features in the cortex and subcortical white matter, together with oligodendrocyte\u2010lineage and myelination defects in the subcortical white matter. Single\u2010cell RNA sequencing showed that astrocytes displayed the most pronounced transcriptional response to CH, identifying them as a major TH\u2010responsive cell type under CH conditions. Notably, a COL11A2\u2010enriched differentiated astrocyte state, Astro\u20102, was virtually absent in CH brains. COL11A2 was further validated as a target of the TH\/TH\u2010receptors (TRs) axis, and its dysregulation impaired astrocyte differentiation and morphological maturation in mice, pigs, and humans. Our findings suggest an association between endocrine regulation of astrocyte development and cerebral gyrification, and uncover a COL11A2\u2010mediated mechanism by which TH deficiency disrupts astrocyte differentiation, providing potential insights into CH\u2010associated cortical malformations.<\/jats:p>","DOI":"10.1002\/advs.77598","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T04:25:12Z","timestamp":1789619112000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["TH\/TRs\u2013\n                    <i>COL11A2<\/i>\n                    Axis Mediates Loss of a Differentiated Astrocyte State in Hypogyrified Brains"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8526-9636","authenticated-orcid":false,"given":"Ying","family":"Zhang","sequence":"first","affiliation":[{"name":"Key Laboratory of Organ Regeneration and Reconstruction Institute of Zoology 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Sciences  Beijing China"},{"name":"Beijing Institute for Stem Cell and Regenerative Medicine  Beijing China"},{"name":"University of Chinese Academy of Sciences  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiani","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Animal Genetics Breeding and Reproduction College of Animal Science South China Agricultural University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Ren","sequence":"additional","affiliation":[{"name":"Key Laboratory of Organ Regeneration and Reconstruction Institute of Zoology Chinese Academy of Sciences  Beijing China"},{"name":"Beijing Institute for Stem Cell and Regenerative Medicine  Beijing China"},{"name":"University of Chinese Academy of Sciences  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongjiang","family":"Yang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Organ Regeneration and Reconstruction Institute of Zoology Chinese Academy of Sciences  Beijing China"},{"name":"Beijing Institute for Stem Cell and Regenerative Medicine  Beijing China"},{"name":"University of Chinese Academy of Sciences  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zichen","family":"Yang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Organ Regeneration and Reconstruction Institute of Zoology Chinese Academy of Sciences  Beijing China"},{"name":"Beijing Institute for Stem Cell and Regenerative Medicine  Beijing China"},{"name":"University of Chinese Academy of Sciences  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guosong","family":"Qin","sequence":"additional","affiliation":[{"name":"Key Laboratory of Organ Regeneration and Reconstruction Institute of Zoology Chinese Academy of Sciences  Beijing China"},{"name":"Beijing Institute for Stem Cell and Regenerative Medicine  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naishi","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Endocrinology Key Laboratory of Endocrinology of National Health Commission Peking Union Medical College Hospital Chinese Academy of Medical Sciences and Peking Union Medical College  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1492-6771","authenticated-orcid":false,"given":"Yanfang","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Animal Biotech Breeding Institute of Animal Science Chinese Academy of Agricultural Sciences (CAAS)  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7893-0721","authenticated-orcid":false,"given":"Jianwei","family":"Jiao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Organ Regeneration and Reconstruction 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