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bioRxiv · 10.64898/2026.06.23.733966

X chromosome inactivation as a novel mechanism for chondrogenesis

Ueharu, H.·Pan, H.·Khehra, S.·Kalantry, S.·Mishina, Y.
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Abstract

X chromosome inactivation (X-inactivation) is generally regarded as a dosage-compensation mechanism restricted to female mammals. Here we show that BMP signaling induces X-inactivation through upregulation of Xist and promotes chondrogenesis in both sexes. Remarkably, augmented BMP signaling induced ectopic X-inactivation: transiently inactivating both X chromosomes in females and one in males in a tissue-specific manner. In cranial neural crest cells, ectopic X-inactivation suppressed X-linked gene Tmsb4x, leading to ectopic cartilage formation. Genetic reduction of Xist or pharmacological restoration of the Tmsb4x product suppressed this phenotype. Moreover, we identified ectopic X-inactivation in SOX9-positive chondroprogenitors during wild-type forelimb development in both sexes. Inhibition of X-inactivation disrupts proximodistal limb patterning ex vivo. These findings establish X-inactivation as a signaling-dependent developmental mechanism linking chromosome-scale gene alterations to skeletal fate specification.

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Ueharu, H., Pan, H., Khehra, S., Kalantry, S., Mishina, Y.. 2026-06-23. X chromosome inactivation as a novel mechanism for chondrogenesis. https://doi.org/10.64898/2026.06.23.733966

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