Nuclear Receptors in Leydig Cell Gene Expression and Function1

Abstract

Several signals, such as hormones and signaling molecules, have been identified as important regulators of Leydig cell differentiation and function. Conveying these signals and translating them into a genomic response to ensure an accurate physiological output requires the action of a network of transcription factors, including those belonging to the nuclear receptor superfamily. Nuclear receptors regulate expression of genes important for growth, differentiation, development, and homeostasis. Several nuclear receptors, such as steroid hormone receptors (NR3A and NR3C families), are activated upon ligand binding, whereas others, including members of the NR2C, NR2F, and NR4A families, either do not require a ligand or ligands have yet to be identified. Several nuclear receptors (e.g., NR2F2 and NR5A1) have been shown to play essential roles in Leydig cells, whereas for others (e.g., NR2B1 and NR4A1), the assessment of their function has been precluded by the early embryonic lethality associated with null mice or by redundancy mechanisms by other family members. This is now being overcome with the generation of novel approaches, including Leydig cell-specific knockout models. This review provides an overview of the nuclear receptor family of transcription factors as they relate to Leydig cell gene expression and function.

GATA4 knockdown in MA-10 Leydig cells identifies multiple target genes in the steroidogenic pathway

“…Whether NR2F2 directly targets steroidogenic genes in Leydig cells, however, remains to be shown (Martin & Tremblay 2010). NR4A2 belongs to the NR4A family of nuclear receptors that have been shown to activate several promoters active in Leydig cells including Star, HSD3B2, Hsd3b1, and Cyp17a1 (Martin & Tremblay 2010). Interestingly, the targets putatively regulated by JUN and NR4A proteins were identified as downregulated targets in our screening of GATA4-deficient MA-10 cells.…”

“…Homozygous male mice carrying a conditional Nr2f2 deletion are infertile due to deficits in Leydig cell differentiation and reduced testosterone production (Qin et al 2008). Whether NR2F2 directly targets steroidogenic genes in Leydig cells, however, remains to be shown (Martin & Tremblay 2010). NR4A2 belongs to the NR4A family of nuclear receptors that have been shown to activate several promoters active in Leydig cells including Star, HSD3B2, Hsd3b1, and Cyp17a1 (Martin & Tremblay 2010).…”

Localization and expression patterns of prolactin-like protein J in mouse testis

“…Testosterone production by Leydig cells is regulated by complex interplay between multiple molecules including those involved in endocrine and paracrine signaling, and proper regulation is critical for optimum reproductive capacity. As a result, a number of Leydig cell-specific genes have been identified as important regulators of reproductive processes (26)(27)(28)(29)(30). As PLP-J is specifically expressed in Leydig cells of the testis and its expression peaks in the adult, similar to the expression pattern of testosterone, we hypothesized that PLP-J is also involved in testosterone biogenesis.…”

KLF6 cooperates with NUR77 and SF1 to activate the human INSL3 promoter in mouse MA-10 leydig cells

“…This indicates that in addition to binding to its element, KLF6 requires the presence of additional factor(s) that are common to Leydig and Sertoli cells but absent from fibroblasts. Transcription factors known to be present in both Sertoli and Leydig cells include the MADS-box factors MEF2 (Daems et al 2014), the zinc finger factor GATA4 (reviewed in Viger et al 2008) and the nuclear receptors SF1 (reviewed in Schimmer & White 2010) and NUR77 (reviewed in Martin & Tremblay 2010). Interestingly, the KLF element in the human INSL3 promoter is adjacent to a previously characterized binding site for the nuclear receptors SF1 and NUR77 (Robert et al 2006).…”