title: Biglycan is a novel binding partner of fibroblast growth factor receptor 3c (FGFR3c) in the human testis.
abstract: Regulation of spermatogonial maintenance in the human testis is currently not well understood. One pathway suggested to be involved is activated by fibroblast growth factor receptor 3 (FGFR3), which is expressed in a subset of spermatogonia. FGFR3-activating mutations have been identified in spermatocytic seminoma, thought to originate from clonal expansion of spermatogonia. In this study we aimed to characterize potential binding partners of FGFR3, and specifically its mesenchymal "c" splice isoform, in human spermatogonia. Based on expression patterns and homology to the binding site, we identified FGF1, FGF2, and FGF9 as the best candidates for natural ligands of FGFR3c in the testis. In addition, we screened non-FGF proteins and found that a proteoglycan biglycan (BGN) contains a sequence homologous to the FGFR3c binding site on FGF1, and is expressed in peritubular cells adjacent to FGFR3-expressing spermatogonia. Experiments in a cell-free system confirmed that BGN binds to FGFR3c and FGF1. In conclusion, our findings further clarify the complex regulation of FGFR3c in the human testis. We postulate that BGN is a factor secreted by peritubular cells to modulate FGFR3c signaling and thus contributes to the regulation of spermatogonial maintenance.
authors.affiliation: Department of Growth and Reproduction, Copenhagen University Hospital (Rigshospitalet), Copenhagen DK-2100, Denmark. Electronic address: sofia.boeg.winge@regionh.dk.
authors.forename: S B
authors.initials: SB
authors.lastname: Winge
authors.affiliation: Laboratory of Neural Plasticity, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2100, Denmark.
authors.forename: J
authors.initials: J
authors.lastname: Nielsen
authors.affiliation: Department of Growth and Reproduction, Copenhagen University Hospital (Rigshospitalet), Copenhagen DK-2100, Denmark.
authors.forename: A
authors.initials: A
authors.lastname: Jørgensen
authors.affiliation: Laboratory of Neural Plasticity, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2100, Denmark.
authors.forename: S
authors.initials: S
authors.lastname: Owczarek
authors.affiliation: Department of Growth and Reproduction, Copenhagen University Hospital (Rigshospitalet), Copenhagen DK-2100, Denmark.
authors.forename: K A
authors.initials: KA
authors.lastname: Ewen
authors.affiliation: Department of Growth and Reproduction, Copenhagen University Hospital (Rigshospitalet), Copenhagen DK-2100, Denmark.
authors.forename: J E
authors.initials: JE
authors.lastname: Nielsen
authors.affiliation: Department of Growth and Reproduction, Copenhagen University Hospital (Rigshospitalet), Copenhagen DK-2100, Denmark.
authors.forename: A
authors.initials: A
authors.lastname: Juul
authors.affiliation: Laboratory of Neural Plasticity, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2100, Denmark.
authors.forename: V
authors.initials: V
authors.lastname: Berezin
authors.affiliation: Department of Growth and Reproduction, Copenhagen University Hospital (Rigshospitalet), Copenhagen DK-2100, Denmark.
authors.forename: E
authors.initials: E
authors.lastname: Rajpert-De Meyts
mesh_terms: D058578:Biglycan / Q000378:metabolism*; D005346:Fibroblast Growth Factors / Q000378:metabolism; D006801:Humans; D008297:Male; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013093:Spermatogonia / Q000166:cytology / Q000378:metabolism*; D013737:Testis / Q000166:cytology / Q000378:metabolism*
chemical_list: C546884:BGN protein, human; D058578:Biglycan; D020033:Protein Isoforms; D005346:Fibroblast Growth Factors; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3
keywords: Biglycan; FGFR3; Peritubular cells; Spermatogonia; Testis