Tarja Kinnunen

Extracellular interactome of the FGF receptor-ligand system: Complexities and the relative simplicity of the worm

Fibroblast growth factors (FGFs) and their receptors (FGFRs) regulate a multitude of biological functions in embryonic development and in adult. A major question is how does one family of growth factors and their receptors control such a variety of functions? Classically, specificity was thought to be imparted by alternative splicing of the FGFRs, resulting in isoforms that bind specifically to a subset of the FGFs, and by different saccharide sequences in the heparan sulfate proteoglycan (HSPG) co‐receptor. A growing number of noncanonical co‐receptors such as integrins and neural cell adhesion molecule (NCAM) are now recognized as imparting additional complexity to classic FGFR signaling. This review will discuss the noncanonical FGFR ligands and speculate on the possibility that they provide additional and alternative means to determining the functional specificity of FGFR signaling. We will also discuss how invertebrate models such as C. elegans may advance our understanding of noncanonical FGFR signaling. Developmental Dynamics 238:277–293, 2009.

The Cooperation of FGF Receptor and Klotho Is Involved in Excretory Canal Development and Regulation of Metabolic Homeostasis in Caenorhabditis elegans

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.

N-Glycosylation Regulates Fibroblast Growth Factor Receptor/EGL-15 Activity in Caenorhabditis elegans in Vivo

The regulation of cell function by fibroblast growth factors (FGFs) classically occurs through a dual receptor system of a tyrosine kinase receptor (FGFR) and a heparan sulfate proteoglycan co-receptor. Mutations in some consensus N-glycosylation sites in human FGFR result in skeletal disorders and craniosynostosis syndromes, and biophysical studies in vitro suggest that N-glycosylation of FGFR alters ligand and heparan sulfate binding properties. The evolutionarily conserved FGFR signaling system of Caenorhabditis elegans has been used to assess the role of N-glycosylation in the regulation of FGFR signaling in vivo. The C. elegans FGF receptor, EGL-15, is N-glycosylated in vivo, and genetic substitution of specific consensus N-glycosylation sites leads to defects in the maintenance of fluid homeostasis and differentiation of sex muscles, both of which are phenotypes previously associated with hyperactive EGL-15 signaling. These phenotypes are suppressed by hypoactive mutations in EGL-15 downstream signaling components or activating mutations in the phosphatidylinositol 3-kinase pathway, respectively. The results show that N-glycans negatively regulate FGFR activity in vivo supporting the notion that mutation of N-glycosylation sites in human FGFR may lead to inappropriate activation of the receptor.

Heparan sulfate is essential for neuron migration and axon outgrowth in Caenorhabditis elegans

Introduction  The importance of heparan sulfate proteoglycans (HSPGs) has been highlighted by a number of human genetic disorders associated with mutations in genes encoding for HSPG protein cores or biosynthetic enzymes required for heparan sulfate assembly.