title: E2f4 and E2f5 are essential for the development of the male reproductive system.
abstract: The E2F transcription factors are primarily implicated in the regulation of entry and exit from the cell cycle. However, in vivo studies have established additional roles for E2Fs during organ development and homeostasis. With the goal of addressing the intestinal requirements of E2f4 and E2f5, we crossed mice carrying Vil-cre, E2f4 conditional and E2f5 germline alleles. E2f4 deletion had no detectable effect on intestinal development. However, E2f4f/f;E2f5+/-;Vil-cre males, but not E2f4f/f;Vil-cre littermates, were unexpectedly sterile. This defect was not due to defective spermatogenesis. Instead, the seminiferous tubules and rete testes showed significant dilation, and spermatozoa accumulated aberrantly in the rete testis and efferent ducts. Our data show that these problems result from defective efferent ducts, a tissue whose primary function is to concentrate sperm through fluid absorption. First, Vil-cre expression, and consequent E2F4 loss, was specific to the efferent ducts and not other reproductive tract tissues. Second, the E2f4f/f;E2f5+/-;Vil-cre efferent ducts had completely lost multiciliated cells and greatly reduced levels of critical absorptive cell proteins: aquaporin1, a water channel protein, and clusterin, an endocytic marker. Collectively, the observed testis phenotypes suggest a fluid flux defect. Remarkably, we observed rete testis dilation prior to the normal time of seminiferous fluid production, arguing that the efferent duct defects promote excessive secretory activity within the reproductive tract. Finally, we also detect key aspects of these testis defects in E2f5-/- mice. Thus, we conclude that E2f4 and E2f5 display overlapping roles in controlling the normal development of the male reproductive system.
authors.affiliation: a David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology , Cambridge , MA , USA.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Danielian
authors.affiliation: b Reproductive Biology & Toxicology , Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois , Urbana , IL , USA.
authors.forename: Rex A
authors.initials: RA
authors.lastname: Hess
authors.affiliation: a David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology , Cambridge , MA , USA.
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Lees
mesh_terms: D000818:Animals; D051398:Aquaporin 1 / Q000235:genetics / Q000378:metabolism; D051152:Clusterin / Q000235:genetics / Q000378:metabolism; D003433:Crosses, Genetic; D050704:E2F4 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D050700:E2F5 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012152:Rete Testis / Q000254:growth & development / Q000378:metabolism* / Q000648:ultrastructure; D012671:Seminiferous Tubules / Q000254:growth & development / Q000378:metabolism* / Q000648:ultrastructure; D015398:Signal Transduction; D013091:Spermatogenesis / Q000235:genetics; D013094:Spermatozoa / Q000166:cytology / Q000378:metabolism*
chemical_list: C496021:Aqp1 protein, mouse; C495243:Clu protein, mouse; D051152:Clusterin; D050704:E2F4 Transcription Factor; D050700:E2F5 Transcription Factor; C493763:E2f4 protein, mouse; C490490:E2f5 protein, mouse; D051398:Aquaporin 1; C045073:Cre recombinase; D019426:Integrases
keywords: E2F4; E2F5; cilia; efferent ducts; fertility; intestine; multiciliated; rete; testis; villin
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