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Biglycan is a novel binding partner of fibroblast growth factor receptor 3c (FGFR3c) in the human testis
S B Winge1, J Nielsen2, A Jørgensen1
1Department of Growth and Reproduction, Copenhagen University Hospital (Rigshospitalet), Copenhagen DK-2100, Denmark.
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.
Insights
Fibroblast growth factor receptor 3 (FGFR3c) plays a role in human spermatogonial maintenance. Biglycan (BGN) binds to FGFR3c and FGF1, suggesting BGN modulates FGFR3c signaling for sperm cell regulation.
Area of Science:
- Reproductive Biology
- Molecular Endocrinology
- Cell Signaling
Background:
- Spermatogonial maintenance regulation in the human testis is poorly understood.
- Fibroblast growth factor receptor 3 (FGFR3) is implicated, particularly its mesenchymal 'c' splice isoform (FGFR3c).
- FGFR3-activating mutations are found in spermatocytic seminoma, suggesting a role in spermatogonial proliferation.
Purpose of the Study:
- To identify binding partners of FGFR3c in human spermatogonia.
- To elucidate the role of potential ligands in FGFR3c signaling.
- To understand the contribution of FGFR3c to spermatogonial maintenance.
Main Methods:
- Candidate ligand identification based on expression patterns and binding site homology.
- Screening of non-FGF proteins for FGFR3c interaction.
- Cell-free system experiments to confirm binding interactions.
Main Results:
- FGF1, FGF2, and FGF9 were identified as potential natural ligands for FGFR3c.
- Biglycan (BGN), a proteoglycan, was found to bind FGFR3c and FGF1.
- BGN is expressed in peritubular cells adjacent to FGFR3-expressing spermatogonia.
Conclusions:
- Biglycan (BGN) is a novel binding partner for FGFR3c and FGF1.
- BGN, secreted by peritubular cells, may modulate FGFR3c signaling.
- These findings contribute to understanding FGFR3c's role in human spermatogonial maintenance.
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