Abstract
Biosynthesis of testosterone occurs mainly in the testicular Leydig cells. Nur77, an orphan nuclear receptor that is expressed in response to the luteinizing hormone/cyclic adenosine monophosphate (LH/cAMP) signaling pathway, is one of the key factors that regulate steroidogenesis in Leydig cells. The function of Nur77 is modulated through interaction with other proteins. FOXA3, a transcription factor that is crucial for male fertility, is also expressed in Leydig cells. Here, we sought to elucidate the role of FOXA3 in testicular steroidogenesis by focusing on its interaction with Nur77. LH/cAMP signaling induces the onset of steroidogenesis in Leydig cells but has a repressive effect on the expression of FOXA3. Overexpression of FOXA3 in MA-10 Leydig cells repressed cAMP-induced expression of Nur77 and its target steroidogenic genes (StAR, P450c17, and Hsd3β). Furthermore, FOXA3 suppressed Nur77 transactivation of the promoter of steroidogenic genes. In mouse primary Leydig cells, adenovirus-mediated overexpression of FOXA3 had similar effects and resulted in decreased production of testosterone. Taken together, these results suggest the role of FOXA3 in the regulation of steroidogenic genes in Leydig cells and fine-tuning steroidogenesis in the testis.
Highlights
Leydig cells in the testis produce hormones and growth factors that are essential for the development and proper functioning of the male reproductive system [1, 2]
We found that unlike Nur77 expression, the expression of Foxa3 is repressed during cAMP-induced steroidogenesis in Leydig cells. is led us to investigate the effect of FOXA3 on Nur77 expression and International Journal of Endocrinology transactivation and on testicular steroidogenesis
To investigate the responsiveness of FOXA3 to luteinizing hormone/cyclic adenosine monophosphate (LH/cAMP) signaling, we stimulated MA-10 cells with cAMP for different time periods and compared it with the expression of Nur77. e expression of Foxa3 was repressed at 2 h, further repressed at 4 h, and restored at 6 h point of cAMP stimulation (Figure 1(a))
Summary
Leydig cells in the testis produce hormones and growth factors that are essential for the development and proper functioning of the male reproductive system [1, 2]. Testosterone, a pivotal male hormone, is mainly produced in testicular Leydig cells, and its production is regulated by steroidogenic proteins, such as StAR, P450c17, and HSD3B. Among the various transcription factors that regulate the expression of steroidogenic genes, Nur plays a major role [3, 4]. Among the Foxa subfamily of transcription factors, only Foxa is expressed in the testis, mainly in Leydig and postmeiotic germ cells [16, 17]. The function of FOXA3, an important transcription factor associated with male fertility, is poorly understood in testicular Leydig cells
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