title: ETV5 regulates sertoli cell chemokines involved in mouse stem/progenitor spermatogonia maintenance.
abstract: Spermatogonial stem cells are the only stem cells in the body that transmit genetic information to offspring. Although growth factors responsible for self-renewal of these cells are known, the factors and mechanisms that attract and physically maintain these cells within their microenvironment are poorly understood. Mice with targeted disruption of Ets variant gene 5 (Etv5) show total loss of stem/progenitor spermatogonia following the first wave of spermatogenesis, resulting in a Sertoli cell-only phenotype and aspermia. Microarray analysis of primary Sertoli cells from Etv5 knockout (Etv5(-/-)) versus wild-type (WT) mice revealed significant decreases in expression of several chemokines. Chemotaxis assays demonstrated that migration of stem/progenitor spermatogonia toward Etv5(-/-) Sertoli cells was significantly decreased compared to migration toward WT Sertoli cells. Interestingly, differentiating spermatogonia, spermatocytes, and round spermatids were not chemoattracted by WT Sertoli cells, whereas stem/progenitor spermatogonia showed a high and significant chemotactic index. Rescue assays using recombinant chemokines indicated that C-C-motif ligand 9 (CCL9) facilitates Sertoli cell chemoattraction of stem/progenitor spermatogonia, which express C-C-receptor type 1 (CCR1). In addition, there is protein-DNA interaction between ETV5 and Ccl9, suggesting that ETV5 might be a direct regulator of Ccl9 expression. Taken together, our data show for the first time that Sertoli cells are chemoattractive for stem/progenitor spermatogonia, and that production of specific chemokines is regulated by ETV5. Therefore, changes in chemokine production and consequent decreases in chemoattraction by Etv5(-/-) Sertoli cells helps to explain stem/progenitor spermatogonia loss in Etv5(-/-) mice.
authors.affiliation: Department of Veterinary Biosciences, University of Illinois, Urbana, Illinois 61802, USA.
authors.forename: Liz
authors.initials: L
authors.lastname: Simon
authors.forename: Gail C
authors.initials: GC
authors.lastname: Ekman
authors.forename: Thomas
authors.initials: T
authors.lastname: Garcia
authors.forename: Kay
authors.initials: K
authors.lastname: Carnes
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhang
authors.forename: Theresa
authors.initials: T
authors.lastname: Murphy
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Murphy
authors.forename: Rex A
authors.initials: RA
authors.lastname: Hess
authors.forename: Paul S
authors.initials: PS
authors.lastname: Cooke
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Hofmann
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D054410:Chemokine CCL7 / Q000235:genetics / Q000378:metabolism; D054365:Chemokine CXCL5 / Q000235:genetics / Q000378:metabolism; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D019742:Chemokines, CC / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D007150:Immunohistochemistry; D019402:Macrophage Inflammatory Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018945:Monocyte Chemoattractant Proteins / Q000235:genetics / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D034622:RNA Interference; D054389:Receptors, CCR1 / Q000235:genetics / Q000378:metabolism; D012708:Sertoli Cells / Q000378:metabolism*; D013093:Spermatogonia / Q000166:cytology* / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*; D013737:Testis / Q000166:cytology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C491224:Ccl12 protein, mouse; C095218:Ccl9 protein, mouse; D054410:Chemokine CCL7; D054365:Chemokine CXCL5; D018925:Chemokines; D019742:Chemokines, CC; D004268:DNA-Binding Proteins; C513242:Etv5 protein, mouse; D019402:Macrophage Inflammatory Proteins; D018945:Monocyte Chemoattractant Proteins; D054389:Receptors, CCR1; D014157:Transcription Factors
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