The development of craniofacial skeletal structures is fascinatingly complex and elucidation of the underlying mechanisms will not only provide novel scientific insights, but also help develop more effective clinical approaches to the treatment and/or prevention of the numerous congenital craniofacial malformations. To this end, we performed a genome-wide analysis of RNA transcription from non-coding regulatory elements by CAGE-sequencing of the facial mesenchyme of human embryos and cross-checked the active enhancers thus identified against genes, identified by GWAS for the normal range human facial appearance. Among the identified active cis-enhancers, several belonged to the components of the PI3/AKT/mTORC1/autophagy pathway. To assess the functional role of this pathway, we manipulated it both genetically and pharmacologically in mice and zebrafish. These experiments revealed that mTORC1 signaling modulates craniofacial shaping at the stage of skeletal mesenchymal condensations, with subsequent fine-tuning during clonal intercalation. This ability of mTORC1 pathway to modulate facial shaping, along with its evolutionary conservation and ability to sense external stimuli, in particular dietary amino acids, indicate that the mTORC1 pathway may play a role in facial phenotypic plasticity. Indeed, the level of protein in the diet of pregnant female mice influenced the activity of mTORC1 in fetal craniofacial structures and altered the size of skeletogenic clones, thus exerting an impact on the local geometry and craniofacial shaping. Overall, our findings indicate that the mTORC1 signaling pathway is involved in the effect of environmental conditions on the shaping of craniofacial structures.

A N Severtsov Institute of Ecology and Evolution Russian Academy of Sciences Moscow Russia

Astrid Lindgren Children's hospital Stockholm Sweden

Biomechanics Lab Institute of Mechanics Materials and Civil Engineering UCLouvain Louvain la Neuve Belgium

Central European Institute of Technology Brno University of Technology Brno Czech Republic

Centre for Bone and Arthritis Research Institute of Medicine Sahlgrenska Academy at University of Gothenburg Gothenburg Sweden

Department of Biosciences and Nutrition Karolinska Institute Flemingsberg Sweden

Department of Cell and Molecular Biology Karolinska Institutet Stockholm Sweden

Department of Developmental and Comparative Physiology N K Koltsov Institute of Developmental Biology Russian Academy of Sciences Moscow Russia

Department of Materials Engineering KU Leuven Leuven Belgium

Department of Neuroimmunology Center for Brain Research Medical University of Vienna Vienna Austria

Department of Neuroscience Karolinska Institutet Stockholm Sweden

Department of Physiology and Pharmacology Karolinska Institutet Stockholm Sweden

Department of Women's and Children's Health Karolinska Institutet Stockholm Sweden

Endocrinology Research Center Moscow Russia

Intractable Disease Research Center Juntendo University Tokyo Japan

Life Improvement by Future Technologies Center Moscow Russia

Pole of Morphology Institute of Experimental and Clinical Research UCLouvain Woluwe Belgium

Prometheus Division for Skeletal Tissue Engineering KU Leuven Leuven Belgium

Regulatory Genomics Research Center Kazan Federal University Kazan Russia

School of Psychological and Cognitive Sciences PKU IDG McGovern Institute for Brain Research Peking University Beijing China

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$a The development of craniofacial skeletal structures is fascinatingly complex and elucidation of the underlying mechanisms will not only provide novel scientific insights, but also help develop more effective clinical approaches to the treatment and/or prevention of the numerous congenital craniofacial malformations. To this end, we performed a genome-wide analysis of RNA transcription from non-coding regulatory elements by CAGE-sequencing of the facial mesenchyme of human embryos and cross-checked the active enhancers thus identified against genes, identified by GWAS for the normal range human facial appearance. Among the identified active cis-enhancers, several belonged to the components of the PI3/AKT/mTORC1/autophagy pathway. To assess the functional role of this pathway, we manipulated it both genetically and pharmacologically in mice and zebrafish. These experiments revealed that mTORC1 signaling modulates craniofacial shaping at the stage of skeletal mesenchymal condensations, with subsequent fine-tuning during clonal intercalation. This ability of mTORC1 pathway to modulate facial shaping, along with its evolutionary conservation and ability to sense external stimuli, in particular dietary amino acids, indicate that the mTORC1 pathway may play a role in facial phenotypic plasticity. Indeed, the level of protein in the diet of pregnant female mice influenced the activity of mTORC1 in fetal craniofacial structures and altered the size of skeletogenic clones, thus exerting an impact on the local geometry and craniofacial shaping. Overall, our findings indicate that the mTORC1 signaling pathway is involved in the effect of environmental conditions on the shaping of craniofacial structures.

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