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

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

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Figure 1

Elevated BMP/Smad signaling causes midline facial defects via regulating CNCC growth and migration in a stage-dependent manner.

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Elevated BMP/Smad signaling causes midline facial defects via regulating...
(A) Drawing showing the morphogenesis of midfacial structures (upper) and pSmad1/5/9 immunostaining in NP tissues (lower, n = 4). Black dotted lines in the upper panel indicate approximate position of each section in the lower panel. (B) Frontal view of facial structures in control and ca-Acvr1(A11) (abbreviated as ca-A in figures) mutants at NB stage (n = 11). (C) Alcian blue–stained transverse sections and safranin O–stained frontal sections of facial structures (n = 4). (D) Ventral view of whole-mount alizarin red– and Alcian blue–stained heads (n = 9). (E) Lateral and frontal view of DAPI-stained heads (n = 5). (F and G) Acvr1 RNA Scope (F) and pSmad1/5/9 immunostaining (G) of NP tissues (n = 5). (H) Representative immunoblots and quantification results of pSmad1/5/9 and Smad1 in E11.5 NP tissues (n = 4). (I) pH3 immunofluorescence (red), TUNEL staining (green), and quantification results in NP tissues (n ≥ 4). (J) Lateral view (left and middle) and coronal sections (right) of R26RtdTomato-positive embryos at E9 (n =4). White arrowheads indicate dorsal end locations of CNCCs. (K) Explant cultures and quantification of CNCCs emigrating from E8.5 neural crest explants (n = 4). (L) Wound-scratch assay and quantification of cell migration distance of NP cells (n = 5). For all panels, data are represented as means ± SD. *P < 0.05; **P < 0.01; ***P < 0.001, unpaired 2-tailed Student’s t test (H, I, K, and L). Scale bars: 200 μm. NS, nasal septum; Pmx, premaxilla; Bs, basisphenoid; Als, alisphenoid; MxP, maxillary process. White and black arrows indicate midline facial cleft (B, D, and E).