Targeted Disruption of Luteinizing Hormone/Human Chorionic Gonadotropin Receptor Gene

Lei, Zhenmin; Mishra, Suresh; Zou, Wen; Xu, Bao‐Hua; Foltz, Martin; Li, X.; Rao, Ch.V.

doi:10.1210/mend.15.1.0586

Cited by 323 publications

(77 citation statements)

References 70 publications

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“…In genetically hypogonadal LH-deficient GnRHr hpg mice, for example, ALC numbers reach only 10% of control (27). Similarly, although 3␤HSD-expressing PLCs are formed in LHR knockout mice (28), LCs fail to develop further and remain severely hypoplastic (29,30). These results indicate that factors other than LH may act on the putative SLCs to induce LHR expression.…”

Section: Discussionmentioning

confidence: 99%

In search of rat stem Leydig cells: Identification, isolation, and lineage-specific development

Dong

Sottas

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

240

301

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Leydig cells (LCs) are thought to differentiate from spindle-shaped precursor cells that exhibit some aspects of differentiated function, including 3␤-hydroxysteroid dehydrogenase (3␤HSD) activity. The precursor cells ultimately derive from undifferentiated stem LCs (SLCs), which are postulated to be present in testes before the onset of precursor cell differentiation. We searched for cells in the neonatal rat testis with the abilities to: (i) proliferate and expand indefinitely in vitro (self renew); (ii) differentiate (i.e., 3␤HSD and ultimately synthesize testosterone); and (iii) when transplanted into host rat testes, colonize the interstitium and subsequently differentiate in vivo. At 1 week postpartum, spindle-shaped cells were seen in the testicular interstitium that differed from the precursor cells in that they were 3␤HSD-negative, luteinizing hormone (LH) receptor (LHR)-negative, and platelet-derived growth factor receptor ␣ (PDGFR␣)-positive. These cells were purified from the testes of 1-week-old rats. The cells contained proteins known to be involved in LC development, including GATA4, c-kit receptor, and leukemia inhibitory factor receptor. The putative SLCs expanded over the course of 6 months while remaining undifferentiated. When treated in media that contained thyroid hormone, insulin-like growth factor I, and LH, 40% of the putative SLCs came to express 3␤HSD and to synthesize testosterone. When transplanted into host rat testes from which LCs had been eliminated, the putative SLCs colonized the interstitium and subsequently expressed 3␤HSD, demonstrating their ability to differentiate in vivo. We conclude that these cells are likely to be the sought-after SLCs.c-kit ͉ leukemia inhibitory factor ͉ platelet-derived growth factor receptor ␣ ͉ puberty ͉ steroidogenesis L eydig cells (LCs) are the primary source of testosterone in the male, and their differentiation in the testes during puberty is a signature event in the development of the male body plan. It is hypothesized, but far from proven, that LCs first arise from undifferentiated stem cells [stem LCs (SLCs)] (1-3). It has been suggested that, in rats, the putative SLCs are present in the testis at birth, and that by 11 days postpartum, at least some of their progeny express LC-specific genes and thus become committed to the LC lineage (4, 5).The committed cells subsequently undergo phased transitions through progenitor and immature stages and ultimately to terminally differentiated adult LC stage (6). In particular, progenitor LCs (PLCs) form during days 12-28 postpartum (presumably from SLCs). The PLCs proliferate and also exhibit some aspects of differentiated function, including 3␤-hydroxysteroid dehydrogenase (3␤HSD) activity (7). Luteinizing hormone (LH) receptors (LHRs) first appear as the PLCs differentiate, suggesting that SLCs are likely to be independent of LH control (8). The development of the steroidogenic capacity of PLCs requires stimulation by LH (9). The mitotic activity of PLCs gradually is reduced, and the cells enlarge...

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Section: Discussionmentioning

confidence: 99%

In search of rat stem Leydig cells: Identification, isolation, and lineage-specific development

Dong

Sottas

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

240

301

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“…Moreover, both the SCARKO and the S-AR -/y suggest that -at least as far as progression through meiosis is concerned -the classical AR is the main mediator involved and that alternative signaling pathways bypassing this receptor play no or only a minor role. In fact, the defect in germ cell development observed in the SCARKO and the S-AR -/y is as severe, or even more severe, than the defect observed in a number of models in which testosterone levels in the testis are drastically reduced such as rats treated with silastic implants releasing low doses of testosterone and estradiol [3] or mice in which the gene encoding thesubunit of LH [108] or the gene encoding the LH receptor [109][110][111] is inactivated. Finally, both the SCARKO and the S-AR -/y model stress that progression through meiosis is critically dependent on androgen action.…”

Section: Lessons From Sertoli Cell-selective Knockout Modelsmentioning

confidence: 98%

“…Recent research has mainly emphasized conversion of round into elongated spermatids [2,3,[29][30][31][32][33] and spermiation [12,34,35] as targets that are particularly sensitive to androgen action. Effects of androgens on meiotic progression have been observed, however, in many models in which gonadotropins were reduced to undetectable levels by hypophysectomy, or by pharmacological means [112][113][114], or in which LH [108] or the LH receptor [109][110][111] were more specifically inactivated. In most of these models spermatogenesis proceeds to the pachytene spematocyte level and administration of androgens induces completion of meiosis and formation of spermatids.…”

Section: Lessons From Sertoli Cell-selective Knockout Modelsmentioning

confidence: 99%

Contribution of Recent Transgenic Models and Transcriptional Profiling Studies to Our Understanding of the Mechanisms by which Androgens Control Spermatogenesis

Verhoeven¹,

Denolet²,

Swinnen³

et al. 2008

IEMAMC

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Androgens play a key role in the control of spermatogenesis and interference with their intratesticular secretion and action is a critical element in many contraceptive strategies. Nonetheless, the cellular and molecular mechanisms by which androgens control germ cell development remain poorly understood. Recent transgenic models in which the androgen receptor (AR) is selectively ablated in Sertoli cells show unambiguously that the Sertoli cell is the main target for androgen action in the control of spermatogenesis. A number of additional mouse models have been developed mimicking human diseases in which mutations of the AR cause disturbed fertility without affecting male development. Transcriptional profiling studies in mice with Sertoli cell-selective AR ablation and in some other experimental paradigms have tried to identify androgen-regulated genes relevant to the control of spermatogenesis. The overlap in genes identified in different studies is poor but this may be due mainly to dissimilarities in experimental setup. In all studies, relatively large numbers of genes rather than a few key genes seem to be affected by androgen action. Genes related to tubular restructuring, cell junction dynamics, cytoskeleton, solute transportation and vitamin A metabolism are prominently present. Although further work is obviously needed, it may be anticipated that these studies will result in the identification of subsets of genes that can be used as diagnostic tools as well as in the identification of targets for the development of novel contraceptives.

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“…This adult population of cells secretes androgens essential for male phenotypic and behavioural development and puberty and maintains fertility in the adult. The adult Leydig cells are completely dependent on LH support for both development and adult function; in the absence of LH few adult Leydig cells develop and circulating testosterone levels are barely detectable (O'Shaughnessy et al ., 1998; Baker & O'Shaughnessy, 2001; Lei et al ., 2001; Zhang et al ., 2001). In contrast, the foetal Leydig cells in rodents appear to function largely independently of hormonal support (El Gehani et al ., 1998; O'Shaughnessy et al ., 1998; Baker et al ., 1999; Lei et al ., 2001; Zhang et al ., 2006) although in other species LH (or hCG in humans) is required for foetal androgen production (O'Shaughnessy & Fowler, 2011).…”

Section: Leydig Cellsmentioning

confidence: 99%

Cell‐specific ablation in the testis: what have we learned?

2015

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SummaryTesticular development and function is the culmination of a complex process of autocrine, paracrine and endocrine interactions between multiple cell types. Dissecting this has classically involved the use of systemic treatments to perturb endocrine function, or more recently, transgenic models to knockout individual genes. However, targeting genes one at a time does not capture the more wide‐ranging role of each cell type in its entirety. An often overlooked, but extremely powerful approach to elucidate cellular function is the use of cell ablation strategies, specifically removing one cellular population and examining the resultant impacts on development and function. Cell ablation studies reveal a more holistic overview of cell–cell interactions. This not only identifies important roles for the ablated cell type, which warrant further downstream study, but also, and importantly, reveals functions within the tissue that occur completely independently of the ablated cell type. To date, cell ablation studies in the testis have specifically removed germ cells, Leydig cells, macrophages and recently Sertoli cells. These studies have provided great leaps in understanding not possible via other approaches; as such, cell ablation represents an essential component in the researchers’ tool‐kit, and should be viewed as a complement to the more mainstream approaches to advancing our understanding of testis biology. In this review, we summarise the cell ablation models used in the testis, and discuss what each of these have taught us about testis development and function.

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Targeted Disruption of Luteinizing Hormone/Human Chorionic Gonadotropin Receptor Gene

Cited by 323 publications

References 70 publications

In search of rat stem Leydig cells: Identification, isolation, and lineage-specific development

In search of rat stem Leydig cells: Identification, isolation, and lineage-specific development

Contribution of Recent Transgenic Models and Transcriptional Profiling Studies to Our Understanding of the Mechanisms by which Androgens Control Spermatogenesis

Cell‐specific ablation in the testis: what have we learned?

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