RRC ID 57679
Author Arai HN, Sato F, Yamamoto T, Woltjen K, Kiyonari H, Yoshimoto Y, Shukunami C, Akiyama H, Kist R, Sehara-Fujisawa A.
Title Metalloprotease-Dependent Attenuation of BMP Signaling Restricts Cardiac Neural Crest Cell Fate.
Journal Cell Rep
Abstract In higher vertebrates, cephalic neural crest cells (NCCs) form craniofacial skeleton by differentiating into chondrocytes and osteoblasts. A subpopulation of cephalic NCCs, cardiac NCCs (CNCCs), migrates to the heart. However, CNCCs mostly do not yield skeletogenic derivatives, and the molecular mechanisms of this fate restriction remain elusive. We identify a disintegrin and metalloprotease 19 (Adam19) as a position-specific fate regulator of NCCs. Adam19-depleted mice abnormally form NCC-derived cartilage in their hearts through the upregulation of Sox9 levels in CNCCs. Moreover, NCC-lineage-specific Sox9-overexpressing mice recapitulate CNCC chondrogenesis. In vitro experiments show that Adam19 mediates the cleavage of bone morphogenic protein (BMP) type I receptor Alk2 (Acvr1), whereas pharmacogenetic approaches reveal that Adam19 inhibits CNCC chondrogenesis by suppressing the BMP-Sox9 cascade, presumably through processing Alk2. These findings suggest a metalloprotease-dependent mechanism attenuating cellular responsiveness to BMP ligands, which is essential for both the positional restriction of NCC skeletogenesis and normal heart development.
Volume 29(3)
Pages 603-616.e5
Published 2019-10-15
DOI 10.1016/j.celrep.2019.09.019
PII S2211-1247(19)31196-9
PMID 31618630
MeSH ADAM Proteins / deficiency ADAM Proteins / genetics ADAM Proteins / metabolism* Activin Receptors, Type I / genetics Activin Receptors, Type I / metabolism Animals Bone Morphogenetic Protein 6 / metabolism Cartilage / growth & development Cartilage / metabolism Cartilage / pathology Cell Differentiation Chondrogenesis Embryo, Mammalian / metabolism HEK293 Cells Humans Mice Mice, Knockout Myocardium / cytology Myocardium / metabolism Neural Crest / cytology Neural Crest / metabolism* Proto-Oncogene Proteins c-myc / genetics Proto-Oncogene Proteins c-myc / metabolism SOX9 Transcription Factor / genetics SOX9 Transcription Factor / metabolism Signal Transduction* Up-Regulation
IF 8.109
Mice RBRC04495 RBRC05654