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Changes in mouse femoral head transcriptome after FGFR3 constitutive activation

ABSTRACT: Achondroplasia (ACH), the most common form of human dwarfism is caused by a mutation in the Fibroblast Growth Factor Receptor 3 (FGFR3) gene, resulting in constitutive activation of the receptor. In order to gain insight into molecular mechanisms involved in the physiopathology, a conditional mouse model carrying the Y367C mutation corresponding to the human Y373C TDI mutation was produced (fgfr3neoY367C/+). Crossing these mice with CMV-CRE mice produces dwarf fgfr3Y367C/+ and fgfr3+/+ controls littermates. Dwarf fgfr3Y367C/+ mice exhibited skeletal dysplasia at birth, the phenotype becoming progressively more pronounced as the mice got older, with reduced length of long bone, narrow trunk, short ribs and macrocephaly. Histological examination of epiphyseal growth plates showed a disorganized growth plate, with reduced size of the hypertrophic and proliferative zone and an accelerated secondary ossification center formation (full phenotype description in Pannier S et al, Activating Fgfr3 Y367C mutation causes hearing loss and inner ear defect in a mouse model of chondrodysplasia. Biochimica et biophysica acta 2009; Pannier S et al, Delayed bone age due to a dual effect of FGFR3 mutation in Achondroplasia. Bone 2010; Jonquoy A et al, A novel tyrosine kinase inhibitor restores chondrocyte differentiation and promotes bone growth in a gain-of-function Fgfr3 mouse model. Human molecular genetics 2012; Martin L et al, Constitutively-active FGFR3 disrupts primary cilium length and IFT20 trafficking in various chondrocyte models of achondroplasia. Human molecular genetics 2018).

ORGANISM(S): Mus musculus

PROVIDER: GSE145821 | GEO | 2020/12/31

REPOSITORIES: GEO

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Project description:Endochondral ossification is the process by which the appendicular skeleton, facial bones, vertebrae and medial clavicles are formed and relies on the tight control of chondrocyte maturation. Fibroblast growth factor receptor (FGFR)3 plays a role in bone development and maintenance and belongs to a family of proteins which differ in their ligand affinities and tissue distribution. Activating mutations of the FGFR3 gene lead to craniosynostosis and multiple types of skeletal dysplasia with varying degrees of severity: thanatophoric dysplasia (TD), achondroplasia and hypochondroplasia. Despite progress in the characterization of FGFR3-mediated regulation of cartilage development, many aspects remain unclear. The aim and the novelty of our study was to examine whole gene expression differences occurring in primary human chondrocytes isolated from normal cartilage or pathological cartilage from TD-affected fetuses, using Affymetrix technology. The phenotype of the primary cells was confirmed by the high expression of chondrocytic markers. Altered expression of genes associated with many cellular processes was observed, including cell growth and proliferation, cell cycle, cell adhesion, cell motility, metabolic pathways, signal transduction, cell cycle process and cell signaling. Most of the cell cycle process genes were down-regulated and consisted of genes involved in cell cycle progression, DNA biosynthesis, spindle dynamics and cytokinesis. About eight percent of all modulated genes were found to impact extracellular matrix (ECM) structure and turnover, especially glycosaminoglycan (GAG) and proteoglycan biosynthesis and sulfation. Altogether, the gene expression analyses provide new insight into the consequences of FGFR3 mutations in cell cycle regulation, onset of pre-hypertrophic differentiation and concomitant metabolism changes. Moreover, impaired motility and ECM properties may also provide clues about growth plate disorganization. These results also suggest that many signaling pathways may be directly or indirectly altered by FGFR3 and confirm the crucial role of FGFR3 in the control of growth plate development.

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Changes in mouse femoral head transcriptome after FGFR3 constitutive activation

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