TH/TRs-COL11A2 Axis Mediates Loss of a Differentiated Astrocyte State in Hypogyrified Brains

Congenital hypothyroidism (CH) is a prevalent endocrine disorder associated with cerebral hypogyrification in neonates and young children, yet the vulnerable cell types and underlying molecular mechanisms remain elusive. 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-lineage and myelination defects in the subcortical white matter. Single-cell RNA sequencing showed that astrocytes displayed the most pronounced transcriptional response to CH, identifying them as a major TH-responsive cell type under CH conditions. Notably, a COL11A2-enriched differentiated astrocyte state, Astro-2, was virtually absent in CH brains. COL11A2 was further validated as a target of the TH/TH-receptors (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-mediated mechanism by which TH deficiency disrupts astrocyte differentiation, providing potential insights into CH-associated cortical malformations.