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: 6.27). 11/2008; 135(22):3745-53. DOI: 10.1242/dev.024786
Source: PubMed

ABSTRACT 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.
    Human Reproduction Update 02/2015; 21(3). DOI:10.1093/humupd/dmv008 · 8.66 Impact Factor
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    • "In contrast, constitutively active Notch signaling in gonadal somatic progenitor cells causes loss of FLCs, however, the number of undifferentiated mesenchymal cells is increaseed. These results indicate that active Notch signaling may repress the differentiation of FLCs (Tang et al., 2008). Anti-Mullerian hormone (AMH), also called Mullerian inhibiting substance (MIS) or factor (MIF) belonging to the transforming growth factor-β (TGFβ) family and is responsible for the regression of Mullerian ducts in male fetuses, which is produced by Sertoli cells from the time when the testicular seminiferous cords differentiate until pubertal maturation and also by postnatal granulose cells (Lee and Donahoe, 1993). "
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    ABSTRACT: Leydig cell (LC) is one of the most important somatic cell types in testis, which localized in the interstitium between seminiferous tubules. The major function of Leydig cells is to produce steroid hormone, androgens. LC differentiation exhibits a biphasic pattern in rodent testes, which are divided into two different temporal mature populations, fetal Leydig cells (FLCs) and adult Leydig cells (ALCs). FLCs are transiently present in fetal testes and undergo involution or degeneration after birth. FLCs are completely devoid and replaced by ALCs in adult testes. Comparing to ALCs, FLCs display unique morphology, ultrastructure and functions. The origin of FLCs has been debated for many years, but it is still a mystery. Many factors have been reported regulating the specification, proliferation and differentiation of FLCs. FLCs degenerate in a few weeks postnatally, however, the underlying mechanism is still unknown. In this review, we will focus on the fate determination of FLCs, and summarize the resent progress on the morphology, ultrastructure, function, origin and involution of FLCs.
    02/2011; 6(1). DOI:10.1007/s11515-011-1100-3
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    • "The NOTCH signaling pathway controls numerous cellfate specification events: cell differentiation inhibition, proliferation control, and stem cell number (Lai 2004; Fortini 2009). Furthermore, NOTCH genes have already been described as potential targets for miR-34 miRNAs (Lewis et al. 2003; Ji et al. 2008; Ji et al. 2009), and NOTCH2, which is hardly expressed in germ cells, could play an important role during testis somatic cell differentiation (Dirami et al. 2001; Mori et al. 2003; Tang et al. 2008). All these data led us to hypothesize a possible connection between miR-34c, NOTCH2 down-regulation, and germ cell differentiation. "
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