2. Academic Validation
  3. Metalloprotease-Dependent Attenuation of BMP Signaling Restricts Cardiac Neural Crest Cell Fate

Metalloprotease-Dependent Attenuation of BMP Signaling Restricts Cardiac Neural Crest Cell Fate

  • Cell Rep. 2019 Oct 15;29(3):603-616.e5. doi: 10.1016/j.celrep.2019.09.019.
Hiroyuki N Arai 1,  Fuminori Sato 2,  Takuya Yamamoto 3,  Knut Woltjen 4,  Hiroshi Kiyonari 5,  Yuki Yoshimoto 6,  Chisa Shukunami 6,  Haruhiko Akiyama 7,  Ralf Kist 8,  Atsuko Sehara-Fujisawa 9
Affiliations

Affiliations

  • 1 Department of Regeneration Science and Engineering, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan. Electronic address: arai.hiroyuki.6e@kyoto-u.ac.jp.
  • 2 Department of Regeneration Science and Engineering, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
  • 3 Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan; Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501 Japan; AMED-CREST, AMED 1-7-1 Otemachi, Chiyodaku, Tokyo 100-0004, Japan; Medical Risk Avoidance Based on iPS Cells Team, RIKEN Center for Advanced Intelligence Project (AIP), Kyoto 606-8507, Japan.
  • 4 Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan; Hakubi Center for Advanced Research, Kyoto University, Kyoto 606-8501, Japan.
  • 5 Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe 650-0047, Japan.
  • 6 Department of Molecular Biology and Biochemistry, Division of Dental Sciences, Biomedical Sciences Major, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan.
  • 7 Department of Orthopedic Surgery, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
  • 8 Centre for Oral Health Research, School of Dental Sciences, Newcastle University, Newcastle upon Tyne NE2 4BW, UK; Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
  • 9 Department of Regeneration Science and Engineering, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan. Electronic address: sehara.atsuko.3m@kyoto-u.ac.jp.
PMID: 31618630 DOI: 10.1016/j.celrep.2019.09.019
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.

Keywords

Alk2; Sox9; a disintegrin and metalloprotease 19; bone morphogenic protein; cardiac neural crest cells; skeletogenesis.

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