RT Journal Article
SR Electronic
T1 Augmented BMP signaling commits cranial neural crest cells to a chondrogenic fate by suppressing autophagic β-catenin degradation
JF Science Signaling
JO Sci. Signal.
FD American Association for the Advancement of Science
SP eaaz9368
DO 10.1126/scisignal.aaz9368
VO 14
IS 665
A1 Yang, Jingwen
A1 Kitami, Megumi
A1 Pan, Haichun
A1 Nakamura, Masako Toda
A1 Zhang, Honghao
A1 Liu, Fei
A1 Zhu, Lingxin
A1 Komatsu, Yoshihiro
A1 Mishina, Yuji
YR 2021
UL http://stke.sciencemag.org/content/14/665/eaaz9368.abstract
AB Mutations that constitutively activate the bone morphogenetic protein (BMP) receptor ACVR1 lead to fibrodysplasia ossificans progressiva (FOP), a disease in which patients develop heterotopic bones through endochondral ossification in connective tissues. Yang et al. found that constitutively active ACVR1 caused cranial neural crest cells (CNCCs) in mice to adopt a chondrogenic fate, resulting in ectopic craniofacial cartilage. The increased BMP signaling caused this shift in cell fate by stimulating mTORC1 activity, which suppressed autophagic degradation of β-catenin and promoted chondrogenesis in CNCCs. These findings offer a possible explanation for the craniofacial cartilage abnormalities in FOP patients.Cranial neural crest cells (CNCCs) are a population of multipotent stem cells that give rise to craniofacial bone and cartilage during development. Bone morphogenetic protein (BMP) signaling and autophagy have been individually implicated in stem cell homeostasis. Mutations that cause constitutive activation of the BMP type I receptor ACVR1 cause the congenital disorder fibrodysplasia ossificans progressiva (FOP), which is characterized by ectopic cartilage and bone in connective tissues in the trunk and sometimes includes ectopic craniofacial bones. Here, we showed that enhanced BMP signaling through the constitutively activated ACVR1 (ca-ACVR1) in CNCCs in mice induced ectopic cartilage formation in the craniofacial region through an autophagy-dependent mechanism. Enhanced BMP signaling suppressed autophagy by activating mTORC1, thus blocking the autophagic degradation of β-catenin, which, in turn, caused CNCCs to adopt a chondrogenic identity. Transient blockade of mTORC1, reactivation of autophagy, or suppression of Wnt–β-catenin signaling reduced ectopic cartilages in ca-Acvr1 mutants. Our results suggest that BMP signaling and autophagy coordinately regulate β-catenin activity to direct the fate of CNCCs during craniofacial development. These findings may also explain why some patients with FOP develop ectopic bones through endochondral ossification in craniofacial regions.