Notch signaling maintains Leydig progenitor cells in the mouse testis

The Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
Development (Impact Factor: 6.46). 11/2008; 135(22):3745-53. DOI: 10.1242/dev.024786
Source: PubMed


During testis development, fetal Leydig cells increase their population from a pool of progenitor cells rather than from proliferation of a differentiated cell population. However, the mechanism that regulates Leydig stem cell self-renewal and differentiation is unknown. Here, we show that blocking Notch signaling, by inhibiting gamma-secretase activity or deleting the downstream target gene Hairy/Enhancer-of-split 1, results in an increase in Leydig cells in the testis. By contrast, constitutively active Notch signaling in gonadal somatic progenitor cells causes a dramatic Leydig cell loss, associated with an increase in undifferentiated mesenchymal cells. These results indicate that active Notch signaling restricts fetal Leydig cell differentiation by promoting a progenitor cell fate. Germ cell loss and abnormal testis cord formation were observed in both gain- and loss-of-function gonads, suggesting that regulation of the Leydig/interstitial cell population is important for male germ cell survival and testis cord formation.

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Available from: Jennifer Brennan, May 28, 2014
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    • "While Dhh signalling is important for the initial steps in fetal stem LC (SLC) differentiation, Notch signalling restricts the differentiation of these stem cells. Constitutive activation of Notch signalling in fetal SLC causes a dramatic reduction in FLC number and a concomitant accumulation of undifferentiated mesenchymal cells, presumptive fetal SLC, in the intersititum of the mouse testis (Tang et al., 2008). Differentiated FLC after E13.5 do not seem to be influenced by Notch signalling implicating that Notch signalling rather acts to maintain the stem cell lineage (reviewed in Svingen and Koopman, 2013). "
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    ABSTRACT: BACKGROUND Leydig cells (LC) are the sites of testicular androgen production. Development of LC occurs in the testes of most mammalian species as two distinct growth phases, i.e. as fetal and pubertal/adult populations. In primates there are indications of a third neonatal growth phase. LC androgen production begins in embryonic life and is crucial for the intrauterine masculinization of the male fetal genital tract and brain, and continues until birth after which it rapidly declines. A short post-natal phase of LC activity in primates (including human) termed ‘mini-puberty’ precedes the period of juvenile quiescence. The adult population of LC evolves, depending on species, in mid- to late-prepuberty upon reawakening of the hypothalamic–pituitary–testicular axis, and these cells are responsible for testicular androgen production in adult life, which continues with a slight gradual decline until senescence. This review is an updated comparative analysis of the functional and morphological maturation of LC in model species with special reference to rodents and primates.
    Full-text · Article · Feb 2015 · Human Reproduction Update
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    • "Similarly, suppression of fetal Leydig cell differentiation occurred in the testes of Pdgfrα (platelet derived growth factor receptor α, which is normally expressed in interstitial cells) KO mice [9]. Moreover, when Notch signaling was activated in fetal testes by genetic manipulation, differentiation of fetal Leydig cells was suppressed [10]. In contrast, blocking of Notch signaling resulted in an increase of fetal Leydig cells [10]. "
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    ABSTRACT: Development of the testis begins with the expression of the SRY gene in pre-Sertoli cells. Soon after, testis cords containing Sertoli and germ cells are formed and fetal Leydig cells subsequently develop in the interstitial space. Studies using knockout mice have indicated that multiple genes encoding growth factors and transcription factors are implicated in fetal Leydig cell differentiation. Previously, we demonstrated that the Arx gene is implicated in this process. However, how ARX regulates Leydig cell differentiation remained unknown. In this study, we examined Arx KO testes and revealed that fetal Leydig cell numbers largely decrease throughout the fetal life. Since our study shows that fetal Leydig cells rarely proliferate, this decrease in the KO testes is thought to be due to defects of fetal Leydig progenitor cells. In sexually indifferent fetal gonads of wild type, ARX was expressed in the coelomic epithelial cells and cells underneath the epithelium as well as cells at the gonad-mesonephros border, both of which have been described to contain progenitors of fetal Leydig cells. After testis differentiation, ARX was expressed in a large population of the interstitial cells but not in fetal Leydig cells, raising the possibility that ARX-positive cells contain fetal Leydig progenitor cells. When examining marker gene expression, we observed cells as if they were differentiating into fetal Leydig cells from the progenitor cells. Based on these results, we propose that ARX acts as a positive factor for differentiation of fetal Leydig cells through functioning at the progenitor stage.
    Full-text · Article · Jun 2013 · PLoS ONE
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    • "In the mouse, fetal Leydig cells are derived from progenitor cells found in two distinct spatial sites, the coelomic epithelium and the gonad-mesonephros border [6]. NR5A1 (also known as SF1) expression drives Leydig cell differentiation from progenitor cells, while Notch signaling appears to maintain Leydig cell progenitors in an undifferentiated state [7], [8]. Leydig cell differentiation is enhanced by desert hedgehog (DHH) secretion from Sertoli cells [9]. "
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    ABSTRACT: Fetal testis steroidogenesis plays an important role in the reproductive development of the male fetus. While regulators of certain aspects of steroidogenesis are known, the initial driver of steroidogenesis in the human and rodent fetal testis is unclear. Through comparative analysis of rodent fetal testis microarray datasets, 54 candidate fetal Leydig cell-specific genes were identified. Fetal mouse testis interstitial expression of a subset of these genes with unknown expression (Crhr1, Gramd1b, Itih5, Vgll3, and Vsnl1) was verified by whole-mount in situ hybridization. Among the candidate fetal Leydig cell-specific factors, three receptors (CRHR1, PRLR, and PROKR2) were tested for a steroidogenic function using ex vivo fetal testes treated with receptor agonists (CRH, PRL, and PROK2). While PRL and PROK2 had no effect, CRH, at low (approximately 1 to 10) nM concentration, increased expression of the steroidogenic genes Cyp11a1, Cyp17a1, Scarb1, and Star in GD15 mouse and GD17 rat testes, and in conjunction, testosterone production was increased. Exposure of GD15 fetal mouse testis to a specific CRHR1 antagonist blunted the CRH-induced steroidogenic gene expression and testosterone responses. Similar to ex vivo rodent fetal testes, ≥10 nM CRH exposure of MA-10 Leydig cells increased steroidogenic pathway mRNA and progesterone levels, showing CRH can enhance steroidogenesis by directly targeting Leydig cells. Crh mRNA expression was observed in rodent fetal hypothalamus, and CRH peptide was detected in rodent amniotic fluid. Together, these data provide a resource for discovering factors controlling fetal Leydig cell biology and suggest that CRHR1 activation by CRH stimulates rat and mouse fetal Leydig cell steroidogenesis in vivo.
    Preview · Article · Oct 2012 · PLoS ONE
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