Abstract
FgfrL1 is the fifth member of the fibroblast growth factor receptor (Fgfr) family. Studies with FgfrL1 deficient mice have demonstrated that the gene plays an important role during embryonic development. FgfrL1 knock-out mice die at birth as they have a malformed diaphragm and lack metanephric kidneys. Similar to the classical Fgfrs, the FgfrL1 protein contains an extracellular part composed of three Ig-like domains that interact with Fgf ligands and heparin. However, the intracellular part of FgfrL1 is not related to the classical receptors and does not possess any tyrosine kinase activity. Curiously enough, the amino acid sequence of this domain is barely conserved among different species, with the exception of three motifs, namely a dileucine peptide, a tandem tyrosine-based motif YXXΦ and a histidine-rich sequence. To investigate the function of the intracellular domain of FgfrL1, we have prepared genetically modified mice that lack the three conserved sequence motifs, but instead contain a GFP cassette (FgfrL1ΔC-GFP). To our surprise, homozygous FgfrL1ΔC-GFP knock-in mice are viable, fertile and phenotypically normal. They do not exhibit any alterations in the diaphragm or the kidney, except for a slight reduction in the number of glomeruli that does not appear to affect life expectancy. In addition, the pancreas of both FgfrL1ΔC-GFP knock-in and FgfrL1 knock-out mice do not show any disturbances in the production of insulin, in contrast to what has been suggested by recent studies. Thus, the conserved motifs of the intracellular FgfrL1 domain are dispensable for organogenesis and normal life. We conclude that the extracellular domain of the protein must conduct the vital functions of FgfrL1.
Highlights
Fibroblast growth factor receptor-like 1 (FgfrL1) is a member of the fibroblast growth factor receptor (Fgfr) family [1,2,3,4]
Mutant kidneys show a slight reduction in the number of glomeruli Since FgfrL1 knock-out mice lack the metanephric kidneys [7], we focused on the kidneys of FgfrL1DC-GFP mice
A similar reduction was even found in kidneys from heterozygous FgfrL1 knock-out mice (Fig. 5C). These results suggested that manipulating the copy number of FgfrL1 or the length of the intracellular domain slightly affect the development of the metanephric kidneys
Summary
Fibroblast growth factor receptor-like 1 (FgfrL1) is a member of the fibroblast growth factor receptor (Fgfr) family [1,2,3,4] It is expressed in most tissues, but its biological function appears to be restricted to a very limited number of organs as demonstrated by studies with knock-out animals. FgfrL1 deficient mice develop quite normally to term and are born alive, but they die immediately after birth due to a malformed diaphragm muscle that is too weak to inflate the lungs [5,6] These mice lack both metanephric kidneys [7] and show slight abnormalities in the skeleton, primarily in the skull [6,8]. In knock-out animals, this mesenchymal-to-epithelial differentiation fails and no renal vesicles are formed
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