Abstract
FGFs have traditionally been associated with cell proliferation, morphogenesis, and development; yet, a subfamily of FGFs (FGF19, -21, and -23) functions as hormones to regulate glucose, lipid, phosphate, and vitamin D metabolism with impact on energy balance and aging. In mammals, Klotho and beta-Klotho are type 1 transmembrane proteins that function as obligatory co-factors for endocrine FGFs to bind to their cognate FGF receptors (FGFRs). Mutations in Klotho/beta-Klotho or fgf19, -21, or -23 are associated with a number of human diseases, including autosomal dominant hypophosphatemic rickets, premature aging disorders, and diabetes. The Caenorhabditis elegans genome contains two paralogues of Klotho/beta-Klotho, klo-1, and klo-2. klo-1 is expressed in the C. elegans excretory canal, which is structurally and functionally paralogous to the vertebrate kidney. KLO-1 associates with EGL-15/FGFR, suggesting a role for KLO-1 in the fluid homeostasis phenotype described previously for egl-15/fgfr mutants. Altered levels of EGL-15/FGFR signaling lead to defects in excretory canal development and function in C. elegans. These results suggest an evolutionarily conserved function for the FGFR-Klotho complex in the development of excretory organs such as the mammalian kidney and the worm excretory canal. These results also suggest an evolutionarily conserved function for the FGFR-Klotho axis in metabolic regulation.
Highlights
Unlike the classical FGFs, the endocrine FGFs have low affinity for heparan sulfate and do not require heparan sulfate proteoglycans for efficient FGF receptors (FGFRs) interaction
We have identified the C. elegans orthologues of Klotho/betaKlotho, klo-1 and klo-2, and show that parallel to Klotho/betaKlotho regulating endocrine functions in mammals, klo-1 and klo-2 are expressed in the excretory canal, the intestine and the hypodermis, tissues which are responsible for ion homeostasis in C. elegans. klo-1 expression is regulated by EGL-15 signaling, EGL-15 associates with KLO-1 in vitro, and transgenic overexpression of klo-1 leads to defects in ion balance
The Clr phenotype of the klo-1 animals is weaker than that observed in strong clr-1 mutants or in hyperactive egl-15 mutants, the similarity in the phenotype suggest that consistent with vertebrate Klotho functionally interacting with FGF receptors, KLO-1 interacts with EGL-15/FGFR to regulate excretory canal development and function
Summary
Unlike the classical FGFs, the endocrine FGFs have low affinity for heparan sulfate and do not require heparan sulfate proteoglycans for efficient FGFR interaction. Egl-15/fgfr Signaling Is Required for klo-1 Expression in Excretory Canal—Vertebrate Klotho and beta-Klotho function as obligatory co-factors for endocrine FGFs to bind and activate their cognate FGF receptors.
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