Genotype–Phenotype Correlation of Tracheal Cartilaginous Sleeves and <i>Fgfr2</i> Mutations in Mice

Lam, Austin S.; Liu, Carrie C.; Deutsch, Gail H.; Rivera, Joshua; Perkins, Jonathan A.; Holmes, Greg; Jabs, Ethylin Wang; Cunningham, Michael L.; Dahl, John P.

doi:10.1002/lary.29060

Cited by 10 publications

(9 citation statements)

References 28 publications

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“…Mice heterozygous or homozygous for activating mutations in Fgfr2 (p.C342Y) that cause Crouzon syndrome fail to segment tracheal cartilage resulting in a rigid tracheal sleeve. Prior to segmentation, mutant mice show increased chondrocyte proliferation (Hines et al, 2019; Lam et al, 2021; Peskett et al, 2017).…”

Section: Selected Topics In Genetics Development Regeneration and Dis...mentioning

confidence: 99%

New developments in the biology of fibroblast growth factors

Ornitz

Itoh

2022

WIREs Mechanisms of Disease

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The fibroblast growth factor (FGF) family is composed of 18 secreted signaling proteins consisting of canonical FGFs and endocrine FGFs that activate four receptor tyrosine kinases (FGFRs 1-4) and four intracellular proteins (intracellular FGFs or iFGFs) that primarily function to regulate the activity of voltagegated sodium channels and other molecules. The canonical FGFs, endocrine FGFs, and iFGFs have been reviewed extensively by us and others. In this review, we briefly summarize past reviews and then focus on new developments in the FGF field since our last review in 2015. Some of the highlights in the past 6 years include the use of optogenetic tools, viral vectors, and inducible transgenes to experimentally modulate FGF signaling, the clinical use of small molecule FGFR inhibitors, an expanded understanding of endocrine FGF signaling, functions for FGF signaling in stem cell pluripotency and differentiation, roles for FGF signaling in tissue homeostasis and regeneration, a continuing elaboration of mechanisms of FGF signaling in development, and an expanding appreciation of roles for FGF signaling in neuropsychiatric diseases.

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Section: Selected Topics In Genetics Development Regeneration and Dis...mentioning

confidence: 99%

New developments in the biology of fibroblast growth factors

Ornitz

Itoh

2022

WIREs Mechanisms of Disease

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“…Most of the work with craniosynostosis-associated genetic variants have focused on the bony skull of mouse models for craniosynostosis, or on human cell lines to demonstrate how specific variants alter the processes of proliferation, differentiation, apoptosis, and/or polarity of osteoblast lineage cells as they differentiate. Exceptions include a study of Fgfr2c C342Y/C342Y mice suggesting that many phenotypic aberrations stem from a primary failure of mesenchymal condensation contributing to aberrant cartilage and bone ( Peskett et al, 2017 ), observations of enhanced tracheal cartilage formation in Fgfr2 mouse lines suggesting that abnormal chondrogenesis occurred ( Lam et al, 2021 ; Wang et al, 2005 ), and studies that demonstrate cartilage-autonomous effects of Fgfr2 variants on the septum nasi and other facial cartilages ( Holmes et al, 2018 ; Kim et al, 2021 ). Holmes et al, 2018 found nasal cavity volume reduction and cartilage thickening to contribute significantly to the prenatal midface phenotype in two Apert syndrome mouse models ( Fgfr2 +/S252W and Fgfr2 +/P253R ) and the Crouzon mouse model used here, but that structural and cellular changes resulting in midfacial dysgenesis differ among specific Fgfr2 variants.…”

Section: Discussionmentioning

confidence: 99%

A dysmorphic mouse model reveals developmental interactions of chondrocranium and dermatocranium

Perrine

Pitirri

Durham

et al. 2022

eLife

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The cranial endo- and dermal skeletons, which comprise the vertebrate skull, evolved independently over 470 million years ago and form separately during embryogenesis. In mammals, much of the cartilaginous chondrocranium is transient, undergoing endochondral ossification or disappearing, so its role in skull morphogenesis is not well studied and it remains an enigmatic structure. We provide complete three-dimensional (3D) reconstructions of the laboratory mouse chondrocranium from embryonic day 13.5 through 17.5 using a novel methodology of uncertainty-guided segmentation of phosphotungstic enhanced 3D microcomputed tomography images with sparse annotation. We evaluate the embryonic mouse chondrocranium and dermatocranium in 3D and delineate the effects of a Fgfr2 variant on embryonic chondrocranial cartilages and on their association with forming dermal bones using the Fgfr2cC342Y/+ Crouzon syndrome mouse. We show that the dermatocranium develops outside of and in shapes that conform to the chondrocranium. Results reveal direct effects of the Fgfr2 variant on embryonic cartilage, on chondrocranium morphology, and on the association between chondrocranium and dermatocranium development. Histologically we observe a trend of relatively more chondrocytes, larger chondrocytes, and/or more matrix in the Fgfr2cC342Y/+ embryos at all timepoints before the chondrocranium begins to disintegrate at E16.5. The chondrocrania and forming dermatocrania of Fgfr2cC342Y/+ embryos are relatively large, but a contrasting trend begins at E16.5 and continues into early postnatal (P0 and P2) timepoints, with the skulls of older Fgfr2cC342Y/+ mice reduced in most dimensions compared to Fgfr2c+/+ littermates. Our findings have implications for the study and treatment of human craniofacial disease, for understanding the impact of chondrocranial morphology on skull growth, and potentially on the evolution of skull morphology.

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“…Most of the work with craniosynostosis-associated genetic variants have focused on the bony skull of mouse models for craniosynostosis, or on human cell lines to demonstrate how specific variants alter the processes of proliferation, differentiation, apoptosis, and/or polarity of osteoblast lineage cells as they differentiate. Exceptions include a study of Fgfr2c C342Y/C342Y mice suggesting that many phenotypic aberrations stem from a primary failure of mesenchymal condensation contributing to aberrant cartilage and bone (Peskett et al, 2017), observations of enhanced tracheal cartilage formation in Fgfr2 mouse lines suggesting that abnormal chondrogenesis occurred (Lam et al, 2021; Wang et al, 2005), and studies that demonstrate cartilage-autonomous effects of Fgfr2 variants on the septum nasi and other facial cartilages (Holmes et al, 2018; Kim et al, 2021). Holmes et al (Holmes et al, 2018) found nasal cavity volume reduction and cartilage thickening to contribute significantly to the prenatal midface phenotype in two Apert syndrome mouse models ( Fgfr2 +/S252W and Fgfr2 +/P253R ) and the Crouzon mouse model used here, but that structural and cellular changes resulting in midfacial dysgenesis differ among specific Fgfr2 variants.…”

Section: Discussionmentioning

confidence: 99%

A dysmorphic mouse model reveals developmental interactions of chondrocranium and dermatocranium

Perrine

Pitirri²,

Kawasaki³

et al. 2021

Preprint

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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 StatementWe 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.

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Genotype–Phenotype Correlation of Tracheal Cartilaginous Sleeves and Fgfr2 Mutations in Mice

Cited by 10 publications

References 28 publications

New developments in the biology of fibroblast growth factors

New developments in the biology of fibroblast growth factors

A dysmorphic mouse model reveals developmental interactions of chondrocranium and dermatocranium

A dysmorphic mouse model reveals developmental interactions of chondrocranium and dermatocranium

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