Haploinsufficiency of Runx2 restores the cranial sutures in a mouse model of Pdgfrb -related craniosynostosis

Sep 25, 2025Human molecular genetics

Reduced Runx2 helps reopen skull joints in mice with Pdgfrb-related skull fusion

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Abstract

Pdgfrb+/W565R mice exhibit craniosynostosis and skull-base malformation similar to human overgrowth syndrome due to a specific mutation.

A gain-of-function mutation in PDGFRB (W566R) is associated with distinctive facial features and craniosynostosis in humans.
CRISPR/Cas9 gene editing successfully generated a mouse model reflecting the human disease phenotype.
Mice with haploinsufficiency of RUNX2 display defects in skull and clavicle development due to insufficient bone formation.
Crossing Pdgfrb+/W565R mice with Runx2+/- mice resulted in near complete restoration of cranial sutures and skull base.
Overactivation of Pdgfrb signaling is linked to craniosynostosis through its interaction with Runx2.

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Syndromic forms of craniosynostosis occur as a result of dysregulation of various molecular signaling cascades. In humans, a specific gain-of-function mutation (W566R) in PDGFRB causes a distinctive overgrowth syndrome (OMIM # 616592). Affected individuals exhibit distinctive facial features and craniosynostosis. Using CRISPR/Cas9 gene editing, we generated a mouse model carrying the same pathogenic variant of PDGFRB. The Pdgfrb+/W565R mice exhibited craniosynostosis with skull-base malformation: thus, we successfully recapitulated the human disease phenotype. In humans, haploinsufficiency of RUNX2, a critical transcription factor in osteogenesis, results in defects of the skull and clavicles due to insufficient membranous ossification. Such phenotypes have been well reproduced in Runx2+/- mice. To delineate the molecular mechanisms underlying the development of Pdgfrb-related craniosynostosis, we crossed the Pdgfrb+/W565R mice with Runx2+/- mice. It is noteworthy that the double- mutant mice, i.e. Pdgfrb+/W565R Runx2+/- mice, exhibited near complete restoration of the cranial sutures and skull base. The present observation provides in vivo evidence that overactivation of Pdgfrb signaling leads to craniosynostosis through the effect of Runx2. The phenotypic reversal of the cranial structures suggests that modification of the Pdgfrb-Runx2 signaling cascade might offer a novel therapeutic opportunity for craniosynostosis.

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