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Over 400 million years of cooperation: Untangling the chondrocranium-dermatocranium connection

View ORCID ProfileSusan M. Motch Perrine, View ORCID ProfileM. Kathleen Pitirri, View ORCID ProfileEmily L. Durham, View ORCID ProfileMizuho Kawasaki, View ORCID ProfileHao Zheng, View ORCID ProfileDanny Z. Chen, View ORCID ProfileKazuhiko Kawasaki, View ORCID ProfileJoan T. Richtsmeier
doi: https://doi.org/10.1101/2021.11.24.469914
Susan M. Motch Perrine
1Department of Anthropology, Pennsylvania State University, University Park, PA 16802
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  • For correspondence: qzk2@psu.edu jta10@psu.edu
M. Kathleen Pitirri
1Department of Anthropology, Pennsylvania State University, University Park, PA 16802
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Emily L. Durham
1Department of Anthropology, Pennsylvania State University, University Park, PA 16802
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Mizuho Kawasaki
1Department of Anthropology, Pennsylvania State University, University Park, PA 16802
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Hao Zheng
2Department of Computer Science and Engineering, University of Notre Dame, Notre Dame, IN 46556
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Danny Z. Chen
2Department of Computer Science and Engineering, University of Notre Dame, Notre Dame, IN 46556
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Kazuhiko Kawasaki
1Department of Anthropology, Pennsylvania State University, University Park, PA 16802
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Joan T. Richtsmeier
1Department of Anthropology, Pennsylvania State University, University Park, PA 16802
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  • For correspondence: qzk2@psu.edu jta10@psu.edu
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Abstract

The cranial endo- and dermal skeletons, which comprise the vertebrate skull, evolved independently and form separately during embryogenesis. In mammals, the mostly cartilaginous cranial endoskeleton forms prior to the bony dermatocranium. Many features of the chondrocranium are transient, undergoing endochondral ossification or disappearing, so its role in skull morphogenesis is not understood The fibroblast growth factor (FGF) and receptor (FGFR) signaling pathway contributes significantly to the regulation of osteochondroprogenitor cell function. Mutations in FGFR genes are associated with diseases that impact the skull including dwarfing chondrodyplasia and craniosynostosis syndromes. We investigate the developing chondrocranium and dermatocranium using a mouse model for craniosynostosis carrying a gain of function mutation in Fgfr2 to assess development of these cranial skeleton systems. Dermatocrania and chondrocrania of Fgfr2cC342Y/+ mice and their Fgfr2c+/+ littermates were quantified in 3D from microcomputed tomography images of mouse embryos. Chondrocrania of embryonic mice carrying the Fgfr2 mutation are larger than their Fgfr2c+/+ littermates and include novel extensions of cartilage over the lateral and dorsal aspect of the brain. Like the forming chondrocranium, the embryonic dermatocranium is larger in Fgfr2cC342Y/+ mice throughout embryogenesis but after disappearance of much of the chondrocranium, the dermatocranium becomes progressively smaller relative to Fgfr2c+/+ littermates during postnatal growth. Results reveal the direct effects of this Fgfr2c mutation on embryonic cranial cartilage, the impact of chondrocranial structure on developing dermatocranial elements, the importance of the chondrocranium in decoding the impact of specific genetic variants on head morphogenesis, and the potential for harnessing these effects as therapeutic targets.

Significance Statement We present the first fully complete three-dimensional (3D) reconstructions of the mouse embryonic chondrocranium using a novel methodology of uncertainty guided segmentation of microcomputed tomography images with sparse annotation. We provide 3D reconstructions of chondrocrania of the Fgfr2cC342Y/+ Crouzon syndrome mouse and typically developing littermates for embryonic days 13.5, 14.5, 15.5, 16.5, and 17.5. This is the first study of the effects of an FGFR2 mutation on embryonic chondrocranial cartilage. 3D reconstructions of embryonic dermal bones reveal that the dermatocranium develops outside of, and in shapes that conform to the chondrocranium. Our findings have implications for the study and treatment of human craniofacial disease and for understanding the impact of chondrocranial morphology on the evolution of skull morphology.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Competing Interest Statement: The authors declare they have no relevant financial or non-financial competing interests to report.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted November 25, 2021.
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Over 400 million years of cooperation: Untangling the chondrocranium-dermatocranium connection
Susan M. Motch Perrine, M. Kathleen Pitirri, Emily L. Durham, Mizuho Kawasaki, Hao Zheng, Danny Z. Chen, Kazuhiko Kawasaki, Joan T. Richtsmeier
bioRxiv 2021.11.24.469914; doi: https://doi.org/10.1101/2021.11.24.469914
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Over 400 million years of cooperation: Untangling the chondrocranium-dermatocranium connection
Susan M. Motch Perrine, M. Kathleen Pitirri, Emily L. Durham, Mizuho Kawasaki, Hao Zheng, Danny Z. Chen, Kazuhiko Kawasaki, Joan T. Richtsmeier
bioRxiv 2021.11.24.469914; doi: https://doi.org/10.1101/2021.11.24.469914

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