Pyroglutamylated RFamide peptide (QRFP): Role in early testicular development in relation to Sertoli cell maturation in prepubertal mice

The future fertility of prepubertal boys with cancer may be irreversibly compromised by chemotherapy and/or radiotherapy. Successful spermatogenesis has not been achieved following the xenotransplantation of prepubertal human testis tissue, which is likely due to the failure of somatic cell maturation and function. We used a validated xenograft model to identify the factors required for Leydig and Sertoli cell development and function in immature human testis. Importantly, we compared the maturation status of Sertoli cells in xenografts with that of human testis tissues (n = 9, 1 year-adult). Human fetal testis (n = 6; 14–21 gestational weeks) tissue, which models many aspects of prepubertal testicular development, was transplanted subcutaneously into castrated immunocompromised mice for ~12 months. The mice received exogenous human chorionic gonadotropin (hCG; 20IU, 3×/week). In xenografts exposed continuously to hCG, we demonstrate the maintenance of Leydig cell steroidogenesis, the acquisition of features of Sertoli cell maturation (androgen receptor, lumen development), and the formation of the blood–testis barrier (connexin 43), none of which were present prior to the transplantation or in xenografts in which hCG was withdrawn after 7 months. These studies provide evidence that hCG plays a role in Sertoli cell maturation, which is relevant for future investigations, helping them generate functional gametes from immature testis tissue for clinical application.

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Immature rat seminiferous tubules reconstructed in vitro express markers of Sertoli cell maturation after xenografting into nude mouse hosts

MHR Basic science of reproductive medicine ◽

10.1093/molehr/gap081 ◽

2009 ◽

Vol 16 (2) ◽

pp. 97-110 ◽

Cited By ~ 19

Author(s):

K. Gassei ◽

J. Ehmcke ◽

M.A. Wood ◽

W.H. Walker ◽

S. Schlatt

Keyword(s):

Sertoli Cell ◽

Nude Mouse ◽

Cell Maturation ◽

Seminiferous Tubules ◽

Immature Rat

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Aromatase and 11β-hydroxysteroid dehydrogenase 2 localisation in the testes of pigs from birth to puberty linked to changes of hormone pattern and testicular morphology

Reproduction Fertility and Development ◽

10.1071/rd07136 ◽

2008 ◽

Vol 20 (4) ◽

pp. 505 ◽

Cited By ~ 5

Author(s):

A. Wagner ◽

R. Claus

Keyword(s):

Blood Plasma ◽

Sertoli Cell ◽

Germ Cells ◽

Leydig Cells ◽

Hydroxysteroid Dehydrogenase ◽

Blood Collection ◽

Testicular Development ◽

Post Mortem ◽

Cell Numbers ◽

Testicular Morphology

Oestrogens and glucocorticoids are important for spermatogenesis and are regulated via aromatase for oestradiol synthesis and 11β-hydroxysteroid dehydrogenase 2 (11β-HSD 2) as an inactivator of cortisol. In the present study postnatal changes of these two enzymes were monitored together with testicular development and hormone concentrations. Pigs were assigned to three periods: Weeks 0–5, Weeks 5–11 or Weeks 11–17. In Period 1, groups of four piglets were killed after each week. Blood plasma and testes were sampled immediately post mortem. For Periods 2 and 3, groups of six pigs were fitted with vein catheters for daily blood collection. Testes from all pigs were obtained after killing. Levels of testosterone, oestradiol, LH, FSH and cortisol were determined radioimmunologically. The 11β-HSD 2- and aromatase-expressing cells were stained immunocytochemically. All hormones were maximal 2 weeks after birth. A rise of LH, testosterone and oestradiol occurred again at Week 17. FSH and cortisol remained basal. Parallel to the first postnatal rise, the presence of aromatase and 11β-HSD 2 in Leydig cells increased, together with germ and Sertoli cell numbers. Expression was low from 3 to 5 weeks, was resumed after Week 5 and was maximal at Week 17. The amount of 11β-HSD 2 in germ cells was greatest at birth, decreased thereafter and was absent after Week 3.

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AKAP9 Is Essential for Spermatogenesis and Sertoli Cell Maturation in Mice

Genetics ◽

10.1534/genetics.113.150789 ◽

2013 ◽

Vol 194 (2) ◽

pp. 447-457 ◽

Cited By ~ 16

Author(s):

Kerry J. Schimenti ◽

Sky K. Feuer ◽

Laurie B. Griffin ◽

Nancy R. Graham ◽

Claire A. Bovet ◽

...

Keyword(s):

Sertoli Cell ◽

Cell Maturation

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Waning of Anti-Müllerian Activity: An Early Sign of Sertoli Cell Maturation in the Developing Pig

Biology of Reproduction ◽

10.1095/biolreprod24.4.923 ◽

1981 ◽

Vol 24 (4) ◽

pp. 923-931 ◽

Cited By ~ 37

Author(s):

Dien Tran ◽

Nicole Meusy-Dessolle ◽

Nathalie Josso

Keyword(s):

Sertoli Cell ◽

Early Sign ◽

Cell Maturation

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Smad3 Dosage Determines Androgen Responsiveness and Sets the Pace of Postnatal Testis Development

Endocrinology ◽

10.1210/en.2010-1453 ◽

2011 ◽

Vol 152 (5) ◽

pp. 2076-2089 ◽

Cited By ~ 22

Author(s):

Catherine Itman ◽

Chin Wong ◽

Briony Hunyadi ◽

Matthias Ernst ◽

David A. Jans ◽

...

Keyword(s):

Germ Cell ◽

Sertoli Cell ◽

Pubertal Development ◽

Cell Development ◽

Cell Maturation ◽

Developmentally Regulated ◽

Testis Development ◽

Essentially Normal ◽

Endocrine Factors ◽

Immature Cells

The establishment and maturation of the testicular Sertoli cell population underpins adult male fertility. These events are influenced by hormones and endocrine factors, including FSH, testosterone and activin. Activin A has developmentally regulated effects on Sertoli cells, enhancing proliferation of immature cells and later promoting postmitotic maturation. These differential responses correlate with altered mothers against decapentaplegic (SMAD)-2/3 signaling: immature cells signal via SMAD3, whereas postmitotic cells use both SMAD2 and SMAD3. This study examined the contribution of SMAD3 to postnatal mouse testis development. We show that SMAD3 production and subcellular localization are highly regulated and, through histological and molecular analyses, identify effects of altered Smad3 dosage on Sertoli and germ cell development. Smad3+/− and Smad3−/− mice had smaller testes at 7 d postpartum, but this was not sustained into adulthood. Juvenile and adult serum FSH levels were unaffected by genotype. Smad3-null mice displayed delayed Sertoli cell maturation and had reduced expression of androgen receptor (AR), androgen-regulated transcripts, and Smad2, whereas germ cell and Leydig cell development were essentially normal. This contrasted remarkably with advanced Sertoli and germ cell maturation and increased expression of AR and androgen-regulated transcripts in Smad3+/− mice. In addition, SMAD3 was down-regulated during testis development and testosterone up-regulated Smad2, but not Smad3, in the TM4 Sertoli cell line. Collectively these data reveal that appropriate SMAD3-mediated signaling drives normal Sertoli cell proliferation, androgen responsiveness, and maturation and influences the pace of the first wave of spermatogenesis, providing new clues to causes of altered pubertal development in boys.

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Role of mammalian Y chromosome in sex determination

Philosophical Transactions of the Royal Society of London Series B Biological Sciences ◽

10.1098/rstb.1988.0114 ◽

1988 ◽

Vol 322 (1208) ◽

pp. 63-72 ◽

Cited By ~ 34

Keyword(s):

Cell Differentiation ◽

Sex Determination ◽

Y Chromosome ◽

Sertoli Cell ◽

Sertoli Cells ◽

Sex Reversal ◽

Testicular Development ◽

Chimeric Mouse ◽

Embryonic Gonad

It has long been assumed that the mammalian Y chromosome either encodes, or controls the production of, a diffusible testis-determining molecule, exposure of the embryonic gonad to this molecule being all that is required to divert it along the testicular pathway. My recent finding that Sertoli cells in XX ↔ XY chimeric mouse testes are exclusively XY has led me to propose a new model in which the Y acts cell-autonomously to bring about Sertoli-cell differentiation. I have suggested that all other aspects of foetal testicular development are triggered by the Sertoli cells without further Y-chromosome involvement. This model thus equates mammalian sex determination with Sertoli-cell determination. Examples of natural and experimentally induced sex reversal are discussed in the context of this model.

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