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 5

Reduced Pdgfra expression downstream of histone lactylation is critical for the midline facial defects of ca-Acvr1(A11) mutants.

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Reduced Pdgfra expression downstream of histone lactylation is critical ...
(A) Schematic showing the generation of transgenic mice with a constitutively activated Pdgfra allele PdgfraK/+, PdgfraK/+ mutants (PdgfraK/+;P0-Cre, abbreviated as PraK/+ in figures), and compound mutants (ca-Acvr1(A11)fl/+;PdgfraK/+;P0-Cre, abbreviated as ca-A;PraK/+ in figures). (B) Whole-mount Alcian blue staining (upper) and H&E staining (lower) of embryo heads from control, ca-Acvr1(A11), PdgfraK/+ mutants (PraK/+), and compound mutants (ca-A;PraK/+) at E18.5 and E14.5, respectively (n ≥ 6). Black arrow indicates midline facial cleft. Black arrowheads indicate increased cartilage formation in PdgfraK/+ mutants. (C) pH3 immunofluorescence (red) and TUNEL staining (green), and quantification results in E11.5 NP tissues (n = 6). (D) Lateral view of whole-mount embryo with DAPI staining (left) and without DAPI staining (middle) and coronal sections (right) of control and compound mutants labeled with R26RTdTomato (n = 5). (E) Relative normalized lactate levels in E11.5 NP tissues (n = 6). (F) Representative immunoblots of Pan-Kla and H3K18la in E11.5 NP tissues (n = 6). Results shown are from blots run contemporaneously. (G) Relative mRNA expression of Slc2a1, Slc2a4, Hk1, and Hk2 in E11.5 NP tissues (n = 4). 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 (C) or 1-way ANOVA (E and G). Scale bars: 1 mm (B); 100 μm (C and D).