title: A Sertoli cell-selective knockout of the androgen receptor causes spermatogenic arrest in meiosis.
abstract: Androgens control spermatogenesis, but germ cells themselves do not express a functional androgen receptor (AR). Androgen regulation is thought to be mediated by Sertoli and peritubular myoid cells, but their relative roles and the mechanisms involved remain largely unknown. Using Cre/loxP technology, we have generated mice with a ubiquitous knockout of the AR as well as mice with a selective AR knockout in Sertoli cells (SC) only. Mice with a floxed exon 2 of the AR gene were crossed with mice expressing Cre recombinase ubiquitously or selectively in SC (under control of the anti-Müllerian hormone gene promoter). AR knockout males displayed a complete androgen insensitivity phenotype. Testes were located abdominally, and germ cell development was severely disrupted. In contrast, SC AR knockout males showed normal testis descent and development of the male urogenital tract. Expression of the homeobox gene Pem, which is androgen-regulated in SC, was severely decreased. Testis weight was reduced to 28% of that in WT littermates. Stereological analysis indicated that the number of SC was unchanged, whereas numbers of spermatocytes, round spermatids, and elongated spermatids were reduced to 64%, 3%, and 0% respectively of WT. These changes were associated with increased germ cell apoptosis and grossly reduced expression of genes specific for late spermatocyte or spermatid development. It is concluded that cell-autonomous action of the AR in SC is an absolute requirement for androgen maintenance of complete spermatogenesis, and that spermatocyte/spermatid development/survival critically depends on androgens.
authors.affiliation: Laboratory for Experimental Medicine and Endocrinology, Department of Developmental Biology, Flanders Interuniversity Institute for Biotechnology, Catholic University of Leuven, B-3000 Leuven, Belgium.
authors.forename: Karel
authors.initials: K
authors.lastname: De Gendt
authors.forename: Johannes V
authors.initials: JV
authors.lastname: Swinnen
authors.forename: Philippa T K
authors.initials: PT
authors.lastname: Saunders
authors.forename: Luc
authors.initials: L
authors.lastname: Schoonjans
authors.forename: Mieke
authors.initials: M
authors.lastname: Dewerchin
authors.forename: Ann
authors.initials: A
authors.lastname: Devos
authors.forename: Karen
authors.initials: K
authors.lastname: Tan
authors.forename: Nina
authors.initials: N
authors.lastname: Atanassova
authors.forename: Frank
authors.initials: F
authors.lastname: Claessens
authors.forename: Charlotte
authors.initials: C
authors.lastname: Lécureuil
authors.forename: Walter
authors.initials: W
authors.lastname: Heyns
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Florian
authors.initials: F
authors.lastname: Guillou
authors.forename: Richard M
authors.initials: RM
authors.lastname: Sharpe
authors.forename: Guido
authors.initials: G
authors.lastname: Verhoeven
mesh_terms: D000818:Animals; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D008540:Meiosis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D011944:Receptors, Androgen / Q000502:physiology*; D012708:Sertoli Cells / Q000502:physiology*; D013091:Spermatogenesis; D013739:Testosterone / Q000097:blood
chemical_list: D011944:Receptors, Androgen; D013739:Testosterone; D007986:Luteinizing Hormone