Rapamycin rescues BMP mediated midline craniosynostosis phenotype through reduction of mTOR signaling in a mouse model

Abstract

Craniosynostosis is defined as congenital premature fusion of one or more cranial sutures. While the genetic basis for about 30% of cases is known, the causative genes for the diverse presentations of the remainder of cases are unknown. The recently discovered cranial suture stem cell population affords an opportunity to identify early signaling pathways that contribute to craniosynostosis. We previously demonstrated that enhanced BMP signaling in neural crest cells (caA3 mutants) leads to premature cranial suture fusion resulting in midline craniosynostosis. Since enhanced mTOR signaling in neural crest cells leads to craniofacial bone lesions, we investigated the extent to which mTOR signaling is involved in the pathogenesis of BMP-mediated craniosynostosis by affecting the suture stem cell population. Our results demonstrate a loss of suture stem cells in the caA3 mutant mice by the newborn stage. We have found increased activation of mTOR signaling in caA3 mutant mice during embryonic stages, but not at the newborn stage. Our study demonstrated that inhibition of mTOR signaling via rapamycin in a time specific manner partially rescued the loss of the suture stem cell population. This study provides insight into how enhanced BMP signaling regulates suture stem cells via mTOR activation.

Signaling Mechanisms Underlying Genetic Pathophysiology of Craniosynostosis

“…A study published recently implied that, when enhancing the expression of BMP signaling in neural crest cells, loss of suture mesenchymal stem cells have been observed. Moreover, higher degree of cell death has also been illustrated in mutant mice 43. Although studies published till now are far from making a conclusion, a speculation could be provided here is that depletion of mesenchymal stem cells within cranial sutures resulted from cell death /apoptosis might be a cellular mechanism of suture premature fusion.…”

“…Studies have been processed for years to investigate the correlations between craniosynostosis and dysregulation of cellular proliferation and differentiation, while the role of apoptosis of cells during cranial development have been proposed by some authors 39-43. Studies indicated that apoptosis is involved in the development of both nasal cartilage and calvarial bones 44, 45.…”

“…Premature fusion of anterior frontal suture has been depicted in BMPR1a mice, whose expression of BMP signaling has been specifically enhanced in neural crest derived tissues, and increased apoptosis was observed in cranial bones 45. Meanwhile, the critical role of apoptosis in cranial sutures have also been illustrated 40, 42, 43. Opperman et al 42 found that additional of TGF- β3 might prevent suture obliteration with less apoptotic cell within sutures.…”

Polycystin‐1 regulates cell proliferation and migration through AKT/mTORC2 pathway in a human craniosynostosis cell model

“…59,60 Furthermore, mTOR signalling was shown to play a critical role in craniofacial development since mTOR disruption in mesoderm-derived mesenchymal cells was found to inhibit long bone development and cause calvarial defects. 58 Of interest, PC1 has been shown to regulate the mTOR signalling pathway in ADPKD studies 37,38,55,57 with mTORC1 further downregulating the expression of PC1 via a feedback loop. 56 A previous study from our research team has demonstrated a connection between polycystins and mTOR signalling in colorectal cancer.…”

“…mTORC1 and mTORC2 are considered as critical regulators of early embryonic development, since disruption of their key components, Raptor or Rictor results in early embryonic death prior to craniofacial organogenesis 59,60 . Furthermore, mTOR signalling was shown to play a critical role in craniofacial development since mTOR disruption in mesoderm‐derived mesenchymal cells was found to inhibit long bone development and cause calvarial defects 58 …”