Hox/Meis-dependent gene-regulatory transition underlies cardiopharyngeal neural crest diversification
Abstract Neural crest cells (NCCs) are multipotent migratory cells essential for cardiac development, yet the lineage trajectories and gene regulatory networks underlying their differentiation in the cardiopharyngeal region remain unclear. Here, we integrate single-cell RNA-seq, spatial transcriptomics, and multiomic analyses to construct a comprehensive map of NCC lineages in developing mouse cardiopharyngeal tissues. We identify a transition from Hox -positive pharyngeal NCCs to Hox -negative intracardiac populations associated with the outflow tract cushion, accompanied by a shift in Meis transcription factor binding and gene-regulatory network architecture. By contrast, NCCs forming the aorticopulmonary septum and great vessel smooth muscle retain distinct Hox -codes. A Meis2 – Sox9 – Scx gene-regulatory network defines a skeletogenic progenitor-like intermediate state that gives rise to coronary artery smooth muscle and semilunar valves. Our findings suggest that the loss of Hox -dependent regional identity enables pharyngeal NCCs to acquire new fates upon entering the cardiac cushion, providing insight into the developmental origins of coronary and valvular calcification.
Authors
- Hiroyuki Aburatani (ORCID: https://orcid.org/0000-0003-0438-1544)
- Kazuhiro Matsui (ORCID: https://orcid.org/0000-0003-0634-2194)
- Yunce Wang
- Haruhiko Akiyama (ORCID: https://orcid.org/0000-0002-5661-9895)
- Shiro Fukuda (ORCID: https://orcid.org/0000-0002-0065-662X)
- Chisa Shukunami (ORCID: https://orcid.org/0000-0001-5616-6761)
- Yasunobu Uchijima
- Masahide Seki (ORCID: https://orcid.org/0000-0001-6091-8698)
- Youichiro Wada (ORCID: https://orcid.org/0000-0003-4543-5991)
- Mayuko Kida
- Daiki Seya (ORCID: https://orcid.org/0000-0002-1319-177X)
- Teruhisa Kawamura (ORCID: https://orcid.org/0000-0002-5759-0246)
- Hiroki Kurihara (ORCID: https://orcid.org/0000-0002-6476-5593)
- Takahide Kohro (ORCID: https://orcid.org/0000-0002-8400-4177)
- Yukihiro Harada
- Hiroki Higashiyama (ORCID: https://orcid.org/0000-0003-1324-8139)
- Akinori Kanai (ORCID: https://orcid.org/0000-0003-1555-6768)
- Hiroto Katoh (ORCID: https://orcid.org/0000-0001-9440-728X)
- Akiyasu Iwase (ORCID: https://orcid.org/0000-0001-9095-5879)
- Sachiko Miyagawa‐Tomita (ORCID: https://orcid.org/0000-0001-6646-8368)
- Yukiko Kurihara (ORCID: https://orcid.org/0000-0002-7954-7433)
- Osamu Nakagawa (ORCID: https://orcid.org/0000-0002-3858-6903)
- Shumpei Ishikawa (ORCID: https://orcid.org/0000-0002-3309-2330)
- Akashi Taguchi
- Shogo Yamamoto
- Seitaro Nomura
- Yutaka Suzuki
Institutions
- Hiroshima University (JP)
- Teikyo Heisei University (JP)
- Ritsumeikan University (JP)
- Jichi Medical University (JP)
- Tokyo University of Science (JP)
- Kagawa Nutrition University (JP)
- National Cerebral and Cardiovascular Center (JP)
- Chiba Cancer Center (JP)
- National Cancer Center Hospital East (JP)
- Kumamoto Medical Center (JP)
- Gifu University (JP)
- The University of Tokyo (JP)
- Kumamoto University (JP)
Publication Details
- Journal
- The EMBO Journal
- Published
- 2026-09-15
- DOI
- https://doi.org/10.1038/s44318-026-00886-x
- Primary Topic
- Congenital heart defects research
- Type
- article
- Field-Weighted Citation Impact
- 0.00