Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
A BMP-controlled metabolic/epigenetic signaling cascade directs midfacial morphogenesis
Jingwen Yang, … , Lorin E. Olson, Yuji Mishina
Jingwen Yang, … , Lorin E. Olson, Yuji Mishina
Published March 11, 2024
Citation Information: J Clin Invest. 2024;134(8):e165787. https://doi.org/10.1172/JCI165787.
View: Text | PDF
Research Article Development Article has an altmetric score of 3

A BMP-controlled metabolic/epigenetic signaling cascade directs midfacial morphogenesis

  • Text
  • PDF
Abstract

Craniofacial anomalies, especially midline facial defects, are among the most common birth defects in patients and are associated with increased mortality or require lifelong treatment. During mammalian embryogenesis, specific instructions arising at genetic, signaling, and metabolic levels are important for stem cell behaviors and fate determination, but how these functionally relevant mechanisms are coordinated to regulate craniofacial morphogenesis remain unknown. Here, we report that bone morphogenetic protein (BMP) signaling in cranial neural crest cells (CNCCs) is critical for glycolytic lactate production and subsequent epigenetic histone lactylation, thereby dictating craniofacial morphogenesis. Elevated BMP signaling in CNCCs through constitutively activated ACVR1 (ca-ACVR1) suppressed glycolytic activity and blocked lactate production via a p53-dependent process that resulted in severe midline facial defects. By modulating epigenetic remodeling, BMP signaling–dependent lactate generation drove histone lactylation levels to alter essential genes of Pdgfra, thus regulating CNCC behavior in vitro as well as in vivo. These findings define an axis wherein BMP signaling controls a metabolic/epigenetic cascade to direct craniofacial morphogenesis, thus providing a conceptual framework for understanding the interaction between genetic and metabolic cues operative during embryonic development. These findings indicate potential preventive strategies of congenital craniofacial birth defects via modulating metabolic-driven histone lactylation.

Authors

Jingwen Yang, Lingxin Zhu, Haichun Pan, Hiroki Ueharu, Masako Toda, Qian Yang, Shawn A. Hallett, Lorin E. Olson, Yuji Mishina

×

Figure 2

Enhanced BMP/Smad signaling suppresses glycolytic activity and reduces lactate-derived histone lactylation in CNCCs during midline facial development.

Options: View larger image (or click on image) Download as PowerPoint
Enhanced BMP/Smad signaling suppresses glycolytic activity and reduces l...
(A) Expression profiles of the metabolites associated with glucose metabolism in NP cells (n = 3). The color bar shows the fold change from the mean of all triplicate samples. (B) Relative normalized (norm.) lactate levels in E11.5 NP tissues (n ≥ 11). (C) Frontal view of pseudocolor images (16 colors) using ImageJ (NIH) and intensity quantification of fluorescent glucose (2-NDBG) in E11.5 NP tissues (n = 8). (D) ECAR measurements and calculated glycolytic flux and glycolytic capacity in NP cells (n = 6). (E) Representative immunostaining images and intensity quantification of GLUT1 (green, left), HK1 (red, middle), and HK2 (green, right) in E10.5 NP tissues (n = 4). (F) Representative immunoblots of GLUT1, GLUT4, HK1, and HK2 in E11.5 NP tissues (n = 4). Results shown are from blots run contemporaneously. (G) Representative immunoblots of Pan-Kla and H3K18la in E11.5 NP tissues (n = 5). Results shown are from blots run contemporaneously. (H) Pan-Kla (red, left) and H3K18la (red, right) immunostaining in E11.5 NP tissues (n = 4). (I) Representative immunoblots of Pan-Kla and H3K18la in O9-1 cells treated with or without BMP7 (n = 5). Results shown are from blots run contemporaneously. For all panels, data are represented as means ± SD. ***P < 0.001, unpaired 2-tailed Student’s t test (B–E). Scale bars: 100 μm (C, E, and H). G3P, glucose 3-phosphate; F1,6BP, fructose 1,6-bisphosphate; 3BP, 3-phosphoglyceric acid; PEP, phosphoenolpyruvic acid; Ace-CoA, acetyl-CoA.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Posted by 5 X users
9 readers on Mendeley
See more details