Transcriptional profiling of luteinizing hormone receptor-deficient mice before and after testosterone treatment provides insight into the hormonal control of postnatal testicular development and Leydig cell differentiation.
Luteinizing hormone (LH) is a key regulator of male fertility through its effects on testosterone secretion by Leydig cells. Transcriptional control of this is, however, currently poorly understood. Mice in which the LH receptor is knocked out (LuRKO) show reduced testicular size, reduced testosterone, elevated serum LH, and a spermatogenic arrest that can be rescued by the administration of testosterone. Using genome-wide transcription profiling of LuRKO and control testes during postnatal development and following testosterone treatment, we show that the transcriptional effects of LH insensitivity are biphasic, with an early testosterone-independent phase and a subsequent testosterone-dependent phase. Testosterone rescue re-enables the second, testosterone-dependent phase of the normal prepubertal transcription program and permits the continuation of spermatogenesis. Examination of the earliest responses to testosterone highlights six genes that respond rapidly in a dose-dependent fashion to the androgen and that are therefore candidate regulatory genes associated with the testosterone-driven progression of spermatogenesis. In addition, our transcriptional data suggest a model for the replacement of fetal-type Leydig cells by adult-type cells during testicular development in which a testosterone feedback switch is necessary for adult Leydig cell production. LH signaling affects the timing of the switch but is not a strict requirement for Leydig cell differentiation.
Griffin
D K
DK
Department of Biosciences, University of Kent, Canterbury, United Kingdom.
Ellis
P J
PJ
Dunmore
B
B
Bauer
J
J
Abel
M H
MH
Affara
N A
NA
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D020869:Gene Expression Profiling; D007985:Leydig Cells / Q000166:cytology* / Q000378:metabolism; D007986:Luteinizing Hormone / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D051379:Mice; D011974:Receptors, LH / Q000235:genetics; D013091:Spermatogenesis / Q000235:genetics; D013737:Testis / Q000254:growth & development*; D013739:Testosterone / Q000494:pharmacology / Q000502:physiology*; D014158:Transcription, Genetic
D011974:Receptors, LH; D013739:Testosterone; D007986:Luteinizing Hormone