title: Expression of FGFR3 during human testis development and in germ cell-derived tumours of young adults.
abstract: Observations in patients with an activating mutation of fibroblast growth factor receptor 3 (FGFR3) suggest a role for FGFR3 signalling in promoting proliferation or survival of germ cells. In this study, we aimed to identify the FGFR3 subtype and the ontogeny of expression during human testis development and to ascertain whether FGFR3 signalling is linked to germ cell proliferation and the pathogenesis of testicular germ cell tumours (TGCTs) of young adult men. Using RT-PCR, immunohistochemistry and Western blotting, we examined 58 specimens of human testes throughout development for FGFR3 expression, and then compared expression of FGFR3 with proliferation markers (PCNA or Ki67). We also analysed for FGFR3 expression 30 TGCTs and 28 testes containing the tumour precursor cell, carcinoma in situ (CIS). Fetal and adult testes expressed exclusively the FGFR3IIIc isoform. FGFR3 protein expression was restricted to the cytoplasm/plasma membrane of spermatogonia and was most prevalent at mid-gestation, infancy and from puberty onwards. Phosphorylated (p)FGFR was detected in pre-spermatogonia at mid-gestation and in spermatogonia during puberty and in the adult testis. Throughout normal human testis development, expression of FGFR3 did not directly correlate with proliferation markers. In preinvasive CIS cells and in TGCTs, including classical seminoma and embryonal carcinoma, FGFR3IIIc was detected only in a small number of cells, with a heterogeneous expression pattern. FGFR3 is an excellent marker for human pre-/spermatogonia throughout development. Signalling through this receptor is likely associated with spermatogonial survival rather than proliferation. FGFR3 is not expressed in gonocytes and may not be essential to the aetiology of TGCTs stemming from CIS.
authors.affiliation: Department of Growth and Reproduction, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Ewen
authors.forename: Inge A
authors.initials: IA
authors.lastname: Olesen
authors.forename: Sofia B
authors.initials: SB
authors.lastname: Winge
authors.forename: Ana R
authors.initials: AR
authors.lastname: Nielsen
authors.forename: John E
authors.initials: JE
authors.lastname: Nielsen
authors.forename: Niels
authors.initials: N
authors.lastname: Graem
authors.forename: Anders
authors.initials: A
authors.lastname: Juul
authors.forename: Ewa
authors.initials: E
authors.lastname: Rajpert-De Meyts
mesh_terms: D000293:Adolescent; D000328:Adult; D015153:Blotting, Western; D002278:Carcinoma in Situ / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D005333:Fetus / Q000166:cytology / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007124:Immunoenzyme Techniques; D007223:Infant; D007231:Infant, Newborn; D019394:Ki-67 Antigen / Q000235:genetics / Q000378:metabolism; D008297:Male; D009373:Neoplasms, Germ Cell and Embryonal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013736:Testicular Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013737:Testis / Q000166:cytology / Q000378:metabolism*; D055815:Young Adult
chemical_list: D019394:Ki-67 Antigen; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3