Primary cilium projects from cells to provide a communication platform with neighboring cells and the surrounding environment. This is ensured by the selective entry of membrane receptors and signaling molecules, producing fine-tuned and effective responses to the extracellular cues. In this study, we focused on one family of signaling molecules, the fibroblast growth factor receptors (FGFRs), their residence within cilia, and its role in FGFR signaling. We show that FGFR1 and FGFR2, but not FGFR3 and FGFR4, localize to primary cilia of the developing mouse tissues and in vitro cells. For FGFR2, we demonstrate that the ciliary residence is necessary for its signaling and expression of target morphogenic genes. We also show that the pathogenic FGFR2 variants have minimal cilium presence, which can be rescued for the p.P253R variant associated with the Apert syndrome by using the RLY-4008 kinase inhibitor. Finally, we determine the molecular regulators of FGFR2 trafficking to cilia, including IFT144, BBS1, and the conserved T429V430 motif within FGFR2.

• MeSH
• cilie * metabolismus   genetika   MeSH
• epitelové buňky * metabolismus   MeSH
• lidé MeSH
• myši MeSH
• receptor fibroblastových růstových faktorů, typ 1 metabolismus   genetika   MeSH
• receptor fibroblastových růstových faktorů, typ 2 * metabolismus   genetika   MeSH
• signální transdukce * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Achondroplasia is the most common form of human dwarfism caused by mutations in the FGFR3 receptor tyrosine kinase. Current therapy begins at 2 years of age and improves longitudinal growth but does not address the cranial malformations including midface hypoplasia and foramen magnum stenosis, which lead to significant otolaryngeal and neurologic compromise. A recent clinical trial found partial restoration of cranial defects with therapy starting at 3 months of age, but results are still inconclusive. The benefits of achondroplasia therapy are therefore controversial, increasing skepticism among the medical community and patients. We used a mouse model of achondroplasia to test treatment protocols aligned with human studies. Early postnatal treatment (from day 1) was compared with late postnatal treatment (from day 4, equivalent to ~5 months in humans). Animals were treated with the FGFR3 inhibitor infigratinib and the effect on skeleton was thoroughly examined. We show that premature fusion of the skull base synchondroses occurs immediately after birth and leads to defective cranial development and foramen magnum stenosis in the mouse model to achondroplasia. This phenotype appears significantly restored by early infigratinib administration when compared with late treatment, which provides weak to no rescue. In contrast, the long bone growth is similarly improved by both early and late protocols. We provide clear evidence that immediate postnatal therapy is critical for normalization of skeletal growth in both the cranial base and long bones and the prevention of sequelae associated with achondroplasia. We also describe the limitations of early postnatal therapy, providing a paradigm-shifting argument for the development of prenatal therapy for achondroplasia.

• MeSH
• achondroplazie * patologie   farmakoterapie   MeSH
• lebka patologie   účinky léků   MeSH
• lidé MeSH
• modely nemocí na zvířatech * MeSH
• myši MeSH
• receptor fibroblastových růstových faktorů, typ 3 * genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH