Augmented BMP signaling commits cranial neural crest cells to a chondrogenic fate by suppressing autophagic β-catenin degradation

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.

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Modulation of β-catenin levels is critical for cranial neural crest patterning and dispersal into first pharyngeal arch

10.1101/726299 ◽

2019 ◽

Author(s):

Alok Javali ◽

Vairavan Laxmanan ◽

Dasaradhi Palakodeti ◽

Ramkumar Sambasivan

Keyword(s):

Neural Crest ◽

Neural Crest Cells ◽

Mouse Embryos ◽

Pharyngeal Arch ◽

Cranial Neural Crest ◽

Connective Tissues ◽

Pharyngeal Arches ◽

Cell Arrangement ◽

Cranial Neural Crest Cells

AbstractVertebrate cranial neural crest cells (CNCC) are multipotent. Proximal to the source CNCC form the cranial ganglia. Distally, in the pharyngeal arches, they give rise to the craniofacial skeleton and connective tissues. Fate choices are made as CNCC pattern into distinct destination compartments. In spite of this importance, the mechanism patterning CNCC is poorly defined. Here, we report that a novel β-catenin-controlled switch in the cell arrangement is critical in patterning CNCC. In mouse embryos, at the first pharyngeal arch axial level, membrane β-catenin levels correlate with the extent of cell-cell adhesion and thus, with a collective or a dispersed state of CNCC. Using in vitro human neural crest model and chemical modulators of β-catenin levels, we show a requirement for down-modulating β-catenin for the collective-to-dispersed switch. Similarly, in β-catenin gain of function mutant mouse embryos, CNCC fail to disperse, which may underlie their failure to populate first pharyngeal arch. Thus, we show that β-catenin-mediated regulation of CNCC tissue architecture, a previously underappreciated mechanism, underlies the patterning of CNCC into fate-specific compartments.Summary statementThe report shows a crucial step in cranial neural crest patterning. Neural crest cells invading the pharyngeal arches transition from a collective to a dispersed state. This transition in cell arrangement is dependent on membrane β-catenin levels.

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