| RRC ID |
57723
|
| 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
|
| Times Cited |
0
|
| Resource |
| DNA material |
B6N Mouse BAC clone (RDB07573)
B6Ng01-116D03 |
