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

Abstract

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.

Generation of a new mouse line with conditionally activated signaling through the BMP receptor, ACVR1: A tool to characterize pleiotropic roles of BMP functions

“…Histologic observation of L35 mut revealed abnormal tissue condensations in the tongue and surrounding tissues (Figure 3, middle column) indicating formation of ectopic cartilage as we recently reported (Yang et al, 2021). We stained the tissues with Safranin O and fast green to confirm formation of ectopic cartilage in L35 mut while the Meckel's cartilage was hypomorphic (Figure 4a,b, middle F I G U R E 3 Abnormal palatogenesis in A11 mut embryos.…”

“…Despite our attempts to achieve ubiquitous and strong expression of the transgenes by employing the CAG promoter, expression levels of the transgene are low and restricted for L35 (Fukuda et al, 2006) or under detection for A11. We speculate that the transgene in line L35 is expressed in cells including progenitor and/or multipotent population such as neural crest cells and fibro adipogenic progenitor cells, and thus ectopic cartilage and ectopic bones are developed after Cre recombination (Agarwal et al, 2016;Shimono et al, 2011;Valer et al, 2019;Wang et al, 2016;Yang et al, 2021;Yu et al, 2008). In contrast, the transgene in line A11 may be expressed in committed and or more differentiated cells.…”

“…For the potential molecular mechanisms of ectopic cartilage formation found in L35 mut embryos, we recently demonstrated that increased BMP signaling suppresses autophagic activity to lower degradation of β-catenin (Yang et al, 2021). Unlike progenitor cells in limb mesenchyme, reduction in Wnt canonical signaling prompt chondrogenic differentiation of cranial neural crest cells (Yang et al, 2021).…”

“…Despite our intention to achieve ubiquitous expression of the transgene upon Cre-recombination, an expression of the line L35 is somehow restricted and augmentation of signaling levels is within several folds (Fukuda et al, 2006;Yang et al, 2021). Here, we employed a different approach to screen mouse embryonic stem (ES) cells to select clones that express high levels of the transgenic construct.…”

Essential Role of CRIM1 on Endometrial Receptivity in Goat

“…Our results found that CRIM1 negatively regulated the autophagic flux in EECs under P 4 , E 2 and IFN-τ treatments. Previous studies have found that CRIM1 interacts with BMP4/7 at the cell surface and inhibits BMP secretion, and BMP signaling regulates autophagy by mTORC1 activity [ 58 , 59 ]. Based on current knowledge, it seems reasonable to propose that CRIM1 regulates autophagy by targeting BMP signaling in EECs, but our results failed to reveal the detailed molecular mechanism; more research is needed on this topic.…”