Contribution of Leydig and Sertoli Cells to Testosterone Production in Mouse Fetal Testes

Abstract

Testosterone is a final product of androgenic hormone biosynthesis, and Leydig cells are known to be the primary source of androgens. In the mammalian testis, two distinct populations of Leydig cells, the fetal and the adult Leydig cells, develop sequentially, and these two cell types differ both morphologically and functionally. It is well known that the adult Leydig cells maintain male reproductive function by producing testosterone. However, it has been controversial whether fetal Leydig cells can produce testosterone, and the synthetic pathway of testosterone in the fetal testis is not fully understood. In the present study, we generated transgenic mice in which enhanced green fluorescence protein was expressed under the control of a fetal Leydig cell-specific enhancer of the Ad4BP/SF-1 (Nr5a1) gene. The transgene construct was prepared by mutating the LIM homeodomain transcription factor (LHX9)-binding sequence in the promoter, which abolished promoter activity in the undifferentiated testicular cells. These transgenic mice were used to collect highly pure fetal Leydig cells. Gene expression and steroidogenic enzyme activities in the fetal Leydig cells as well as in the fetal Sertoli cells and adult Leydig cells were analyzed. Our results revealed that the fetal Leydig cells synthesize only androstenedione because they lack expression of Hsd17b3, and fetal Sertoli cells convert androstenedione to testosterone, whereas adult Leydig cells synthesize testosterone by themselves. The current study demonstrated that both Leydig and Sertoli cells are required for testosterone synthesis in the mouse fetal testis.

Sertoli cells control peritubular myoid cell fate and support adult Leydig cell development in the prepubertal testis

“…in testosterone production prior to puberty (O'Shaughnessy et al, 2000;Shima et al, 2013). We conclude that, following initial specification, the FLC population is retained and apparently functions relatively normally, independent of SC, GC and PTMC input in fetal and neonatal life.…”

Long-term clinical course in three patients with <i>MAMLD1</i> mutations

“…First, MAMLD1 deficiency may compromise fetal Leydig cell function around the critical period for sex development, leading to 46,XY DSD with hypospadias because of reduced but not abolished T production, as has been proposed previously [1]. In this regard, recent mouse studies have indicated that prenatal T biosynthesis requires both fetal Leydig cells that produce ∆4-androstenedione and Sertoli cells that express Hsd17b3 for the conversion of ∆4-androstenedione into T [20], although such Sertoli cell-specific HSD17B3 expression has not been demonstrated in human fetuses. Thus, in contrast to Mamld1 knockout mice [8], if Sertoli cell function is also compromised in affected patients, this would also contribute to defective T production during fetal life of affected patients.…”

Mapping lineage progression of somatic progenitor cells in the mouse fetal testis

“…Adult Leydig cells maintain androgen production throughout adulthood, functionally replacing fetal Leydig cells (Griswold and Behringer, 2009;Habert et al, 2001). Despite their similar functions in producing androgens, fetal and adult Leydig cells exhibit many differences in their transcriptomes (Dong et al, 2007;Shima et al, 2013), morphology (Haider, 2004) and regulation (Agelopoulou et al, 1984;Aubert et al, 1985;Baker and O'Shaughnessy, 2001;Dong et al, 2007;El-Gehani et al, 1998;Gangnerau and Picon, 1987;Ma et al, 2004;Majdic et al, 1998;O'Shaughnessy et al, 1998;Patsavoudi et al, 1985;Zhang et al, 2001). These differences between fetal and adult Leydig cells led to the hypothesis that the two Leydig cell populations are in fact distinct cell lineages arising from separate origins (Baker et al, 1999;Haider, 2004;Kerr and Knell, 1988;Lording and De Kretser, 1972;O'Shaughnessy et al, 2003;O'Shaughnessy and Fowler, 2011;Roosen-Runge and Anderson, 1959;Shima et al, 2013).…”

“…Despite their similar functions in producing androgens, fetal and adult Leydig cells exhibit many differences in their transcriptomes (Dong et al, 2007;Shima et al, 2013), morphology (Haider, 2004) and regulation (Agelopoulou et al, 1984;Aubert et al, 1985;Baker and O'Shaughnessy, 2001;Dong et al, 2007;El-Gehani et al, 1998;Gangnerau and Picon, 1987;Ma et al, 2004;Majdic et al, 1998;O'Shaughnessy et al, 1998;Patsavoudi et al, 1985;Zhang et al, 2001). These differences between fetal and adult Leydig cells led to the hypothesis that the two Leydig cell populations are in fact distinct cell lineages arising from separate origins (Baker et al, 1999;Haider, 2004;Kerr and Knell, 1988;Lording and De Kretser, 1972;O'Shaughnessy et al, 2003;O'Shaughnessy and Fowler, 2011;Roosen-Runge and Anderson, 1959;Shima et al, 2013). In fact, multiple origins of fetal Leydig cells have been suggested, including Sf1 + nonsteroidogenic interstitial cells originating from the gonadal primordium (Barsoum et al, 2013;Barsoum and Yao, 2010), mesonephros (Merchant-Larios and Moreno-Mendoza, 1998;Val et al, 2006), neural crest (Mayerhofer et al, 1996), coelomic epithelium (Karl and Capel, 1998), and cells residing in the border between gonad and mesonephros (DeFalco et al, 2011).…”