title: Activin signaling regulates Sertoli cell differentiation and function.
abstract: Throughout development, activin A signaling stimulates proliferation and inhibits differentiation of testicular Sertoli cells. A decline in activin levels at puberty corresponds with the differentiation of Sertoli cells that is required to sustain spermatogenesis. In this study, we consider whether terminally differentiated Sertoli cells can revert to a functionally immature phenotype in response to activin A. To increase systemic activin levels, the right tibialis anterior muscle of 7-wk-old C57BL/6J mice was transduced with an adeno-associated virus (rAAV6) expressing activin A. We show that chronic activin signaling reduces testis mass by 23.5% compared with control animals and induces a hypospermatogenic phenotype, consistent with a failure of Sertoli cells to support spermatogenesis. We use permeability tracers and transepithelial electrical resistance measurements to demonstrate that activin potently disrupts blood-testis-barrier function in adult mice and ablates tight junction formation in differentiated primary Sertoli cells, respectively. Furthermore, increased activin signaling reinitiates a program of cellular proliferation in primary Sertoli cells as determined by 5-ethynyl-2'-deoxyuridine incorporation. Proliferative cells reexpress juvenile markers, including cytokeratin-18, and suppress mature markers, including claudin-11. Thus, activin A is the first identified factor capable of reprogramming Sertoli cells to an immature, dedifferentiated phenotype. This study indicates that activin signaling must be strictly controlled in the adult in order to maintain Sertoli cell function in spermatogenesis.
authors.affiliation: Prince Henry's Institute of Medical Research, Clayton 3168, Victoria, Australia.
authors.forename: Peter K
authors.initials: PK
authors.lastname: Nicholls
authors.forename: Peter G
authors.initials: PG
authors.lastname: Stanton
authors.forename: Justin L
authors.initials: JL
authors.lastname: Chen
authors.forename: Justine S
authors.initials: JS
authors.lastname: Olcorn
authors.forename: Jenna T
authors.initials: JT
authors.lastname: Haverfield
authors.forename: Hongwei
authors.initials: H
authors.lastname: Qian
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Walton
authors.forename: Paul
authors.initials: P
authors.lastname: Gregorevic
authors.forename: Craig A
authors.initials: CA
authors.lastname: Harrison
mesh_terms: D028341:Activins / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation; D057167:Claudins / Q000378:metabolism; D000229:Dependovirus / Q000378:metabolism; D005786:Gene Expression Regulation; D053538:Keratin-18 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D010539:Permeability; D051381:Rats; D012708:Sertoli Cells / Q000166:cytology*; D015398:Signal Transduction; D013091:Spermatogenesis; D013737:Testis / Q000473:pathology
chemical_list: D057167:Claudins; C492354:Cldn11 protein, mouse; D053538:Keratin-18; D028341:Activins