Dickkopf-like1 regulates postpubertal spermatocyte apoptosis and testosterone production.
Dickkopf-like1 (Dkkl1) encodes a glycoprotein secreted by postmeiotic male germ cells. We report here that adult Dkkl1-deficient males have elevated sperm counts caused by a decrease in postpubertal spermatocyte apoptosis and display, upon aging, increased local production of testosterone. Molecular analyses identified the Fas death ligand (FasL) as a target for Dkkl1 pro-apoptotic activity in adult mice. Accordingly, adult FasL-deficient gld mice display an increased sperm count and decreased spermatocyte apoptosis phenotype similar to the one observed in Dkkl1-deficient mice. We also show that the elevated testosterone level observed in aging Dkkl1-deficient males is secondary to increased expression in Leydig cells of CYP11A and CYP17, two genes implicated in steroidogenesis. Furthermore, treatment of Leydig cells with Dkkl1 decreases DNA binding and transcriptional activity of steroidogenic factor 1, a pivotal regulator of gene expression in testis. Thus, this study establishes Dkkl1 as a negative regulator of adult testis homeostasis and identifies a novel, Dkkl1/FasL-dependent, regulation that specifically controls the number of postpubertal spermatocytes.
Dakhova
Olga
O
Department of Molecular and Human Genetics, Baylor College of Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
O'Day
Diana
D
Kinet
Noe
N
Yucer
Nur
N
Wiese
Mary
M
Shetty
Gunapala
G
Ducy
Patricia
P
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053222:Fas Ligand Protein / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D013076:Sperm Count; D013090:Spermatocytes / Q000166:cytology / Q000502:physiology*; D013739:Testosterone / Q000096:biosynthesis*; D014162:Transfection
C501127:Dkk1 protein, mouse; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D013739:Testosterone; D012313:RNA