Augmentation of bone morphogenetic protein signaling in cranial neural crest cells in mice deforms skull base due to premature fusion of intersphenoidal synchondrosis

Abstract

Craniofacial anomalies (CFAs) are a diverse group of disorders affecting the shapes of the face and the head. Malformation of the cranial base in humans leads CFAs, such as midfacial hypoplasia and craniosynostosis. These patients have significant burdens associated with breathing, speaking, and chewing. Invasive surgical intervention is the current primary option to correct these structural deficiencies. Understanding molecular cellular mechanism for craniofacial development would provide novel therapeutic options for CFAs. In this study, we found that enhanced bone morphogenetic protein (BMP) signaling in cranial neural crest cells (NCCs) (P0-Cre;caBmpr1a mice) causes premature fusion of intersphenoid synchondrosis (ISS) resulting in leading to short snouts and hypertelorism. Histological analyses revealed reduction of proliferation and higher cell death in ISS at postnatal day 3. We demonstrated to prevent the premature fusion of ISS in P0-Cre;caBmpr1a mice by injecting a p53 inhibitor Pifithrin-α to the pregnant mother from E15.5 to E18.5, resulting in rescue from short snouts and hypertelorism. We further demonstrated to prevent premature fusion of cranial sutures in P0-Cre;caBmpr1a mice by injecting Pifithrin-α through E8.5 to E18.5. These results suggested that enhanced BMP-p53-induced cell death in cranial NCCs causes premature fusion of ISS and sutures in time-dependent manner.

BMP signaling during craniofacial development: new insights into pathological mechanisms leading to craniofacial anomalies

“…We reported that NC-specific expression of caBmpr1a in mice (P0-Cre;caBmpr1a mice) develops premature fusion of the anterior frontal suture and the naso-premaxillary suture, which leads to craniosynostosis (Komatsu et al, 2013;Pan et al, 2017;Kramer et al, 2018;Liu et al, 2018;Ueharu et al, 2023b). We found elevated cell death in cranial NCCs in P0-Cre; caBmpr1a mice, and inhibition of p53-induced cell death partially rescued premature suture fusion (Komatsu et al, 2013;Hayano et al, 2015;Ueharu et al, 2023a;Ueharu et al, 2023b). Of note, ectopic cartilage is developed only in the sutures which prematurely fused, and during the fusion process, the ectopic cartilage is replaced into bone nodules (Ueharu et al, 2023b).…”

Transcriptomic Signatures of Single-Suture Craniosynostosis Phenotypes

“…In a case study of a prenatal diagnosis of de novo pure trisomy 6p (6p22.3 → p25.3) affected with craniosynostosis and microcephaly, the patient had a 20.88 Mb dosage increase in the genomic region containing the gene BMP6 , which led to overexpression of this gene [ 30 ]. Recent studies have revealed that damaging de novo variants of genes within the BMP signaling pathway are associated with lambdoid craniosynostosis in human [ 31 ], and that augmented BMP signaling in mice neural crest cells is associated with premature fusion of intersphenoid synchondroses, resulting in craniofacial anomalies including craniosynostosis [ 32 ]. CLDN11 was significantly increased, compared to controls, in coronal craniosynostosis in males, and was one of the top three increased genes in our male-stratified coronal craniosynostosis model.…”