scholarly journals A missense mutation of the Dhh gene is associated with male pseudohermaphroditic rats showing impaired Leydig cell development

Reproduction ◽  
2011 ◽  
Vol 141 (2) ◽  
pp. 217-225 ◽  
Author(s):  
Yasuhiro Kawai ◽  
Junko Noguchi ◽  
Kouyou Akiyama ◽  
Yuriko Takeno ◽  
Yasuhiro Fujiwara ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Leydig Cell ◽  
Leydig Cells ◽  
Recessive Gene ◽  
Testicular Development ◽  
Specific Marker ◽  
Androgen Deficiency ◽  
Loss Of Function ◽  
Causative Gene ◽  
Mutant Rat

Development of the male gonads is a complex process with interaction of various cells in the gonads including germ, Sertoli, Leydig, and myoid cells. TF is a mutant rat strain showing male pseudohermaphroditism, with agenesis of Leydig cells and androgen deficiency controlled by an autosomal single recessive gene (mp). The mp locus was mapped on the distal region of rat chromosome 7 by linkage analysis, but the gene responsible for the mp mutation has not been identified. In this study, we performed fine linkage mapping and sequence analysis to determine the causative gene of the mp mutation, and performed an immunohistochemical study using a Leydig cell-specific marker to investigate detailed phenotypes of the mutant rats during the testicular development. As a result, we found a missense mutation of the gene encoding Desert hedgehog (Dhh) in the mutant rat, which could result in loss of function of the DHH signaling pathway. Histochemical examination revealed remarkably reduced number of fetal Leydig cells and lack of typical spindle-shaped adult Leydig cell in the mp/mp rats. These phenotypes resembled those of the Dhh-null mice. Additionally, testosterone levels were significantly lower in the mp/mp fetus, indicating androgen deficiency during embryonic development. These results indicate that the mutation of the Dhh gene may be responsible for the pseudohermaphrodite phenotypes of the mutant rat, and that the Dhh gene is probably essential for the development of Leydig cells.

scholarly journals Identification of a compound heterozygote in LYST gene: a case report on Chediak-Higashi syndrome

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Yinsen Song ◽  
Zhengping Dong ◽  
Shuying Luo ◽  
Junmei Yang ◽  
Yuebing Lu ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Genetic Diseases ◽  
Amplicon Sequencing ◽  
Bone Marrow Examination ◽  
Pathogenic Mutation ◽  
Pedigree Analysis ◽  
Compound Heterozygote ◽  
Loss Of Function ◽  
Causative Gene ◽  
Chediak Higashi Syndrome

Abstract Background Chediak-Higashi Syndrome (CHS) is a rare autosomal recessive disease caused by loss of function of the lysosomal trafficking regulator protein. The causative gene LYST/CHS1 was cloned and identified in 1996, which showed significant homology to other species such as bovine and mouse. To date, 74 pathogenic or likely pathogenic mutations had been reported. Case presentation Here we describe a compound heterozygote in LYST gene, which was identified in a 4-year-old female patient. The patient showed skin hypopigmentation, sensitivity to light, mild splenomegaly and reduction of platelets in clinical examination. Giant intracytoplasmic inclusions were observed in the bone marrow examination, suggesting the diagnosis of CHS. Amplicon sequencing was performed to detect pathogenic mutation in LYST gene. The result was confirmed by two-generation pedigree analysis base on sanger sequencing. Conclusion A compound heterozygote in LYST gene, consisting of a missense mutation c.5719A > G and an intron mutation c.4863-4G > A, was identified from the patient by using amplicon sequencing. The missense mutation is reported for the first time. Two-generation pedigree analysis showed these two mutations were inherited from the patient’s parents, respectively. Our result demonstrated that amplicon sequencing has great potential for accelerating and improving the diagnosis of rare genetic diseases.

scholarly journals Wt1 dictates the fate of fetal and adult Leydig cells during development in the mouse testis

2014 ◽  
Vol 307 (12) ◽  
pp. E1131-E1143 ◽  
Author(s):  
Qing Wen ◽  
Qiao-Song Zheng ◽  
Xi-Xia Li ◽  
Zhao-Yuan Hu ◽  
Fei Gao ◽  
...  
Keyword(s):  
Leydig Cell ◽  
Testosterone Level ◽  
Leydig Cells ◽  
Wilms Tumor ◽  
Suppressor Gene ◽  
Testicular Development ◽  
Gene Encoding ◽  
Testis Development ◽  
Adult Mice ◽  
Serum Lh

Wilms' tumor 1 ( Wt1) is a tumor suppressor gene encoding ∼24 zinc finger transcription factors. In the mammalian testis, Wt1 is expressed mostly by Sertoli cells (SCs) involved in testis development, spermatogenesis, and adult Leydig cell (ALC) steroidogenesis. Global knockout (KO) of Wt1 is lethal in mice due to defects in embryogenesis. Herein, we showed that Wt1 is involved in regulating fetal Leydig cell (FLC) degeneration and ALC differentiation during testicular development. Using Wt1−/flox; Amh-Cre mice that specifically deleted Wt1 in the SC vs. age-matched wild-type (WT) controls, FLC-like-clusters were found in Wt1-deficient testes that remained mitotically active from postnatal day 1 (P1) to P56, and no ALC was detected at these ages. Leydig cells in mutant adult testes displayed morphological features of FLC. Also, FLC-like cells in adult mutant testes had reduced expression in ALC-associated genes Ptgds, Sult1e1, Vcam1, Hsd11b1, Hsd3b6, and Hsd17b3 but high expression of FLC-associated genes Thbs2 and Hsd3b1. Whereas serum LH and testosterone level in mutant mice were not different from controls, intratesticular testosterone level was significantly reduced. Deletion of Wt1 gene also perturbed the expression of steroidogenic enzymes Star, P450c17, Hsd3b6, Hsd3b1, Hsd17b1, and Hsd17b3. FLCs in adult mutant testes failed to convert androstenedione to testosterone due to a lack of Hsd17b3, and this defect was rescued by coculturing with fetal SCs. In summary, FLC-like cells in mutant testes are putative FLCs that remain mitotically active in adult mice, illustrating that Wt1 dictates the fate of FLC and ALC during postnatal testis development.

Inhibition of testicular and somatic development after treatment of the postnatal rat with the Leydig cell cytotoxic ethylene dimethanesulphonate

1988 ◽  
Vol 119 (3) ◽  
pp. 467-NP ◽  
Author(s):  
I. D. Morris ◽  
R. G. Lendon ◽  
A. Zaidi
Keyword(s):  
Leydig Cell ◽  
Leydig Cells ◽  
Serum Testosterone ◽  
Male Rats ◽  
Seminiferous Tubules ◽  
Testicular Development ◽  
Interstitial Tissue ◽  
Somatic Development ◽  
Serum Lh ◽  
Loss Of Weight

ABSTRACT The Leydig cell cytotoxic ethylene dimethanesulphonate (EDS) was administered s.c. daily (50 mg/kg) to male rats aged 5–16 days. Apart from loss of weight and that the eyelids unfused earlier, no gross toxicity was observed during treatment. On day 17 testis weights, serum testosterone concentrations, testicular serum testosterone content and 125I-labelled human chorionic gonadotrophin (hCG) binding to testicular homogenates were reduced. Serum LH and FSH concentrations were elevated. The testes did not recover from EDS treatment and at 63 and 120 days were minute (<2% of control), and the prostate and seminal vesicles were small although not completely atrophied. In addition, body weights were substantially reduced. Serum and testicular testosterone and 125I-labelled hCG binding to testicular homogenates were reduced but not absent. Serum LH and FSH concentrations were increased. Light microscopy of the adult testes showed that EDS treatment inhibited the development of the seminiferous tubules. Most of the tubules were devoid of germ cells and Sertoli cells were rare. Occasionally tubules also contained spermatogonia and spermatocytes but no signs of spermiogenesis. The testes were composed mainly of closely packed interstitial tissue with no lymphatic space. The interstitial cells resembled Leydig cells and stained for 3β-hydroxysteroid dehydrogenase. Histochemically identified Leydig cells were absent during treatment but reappeared when treatment was withdrawn. Testicular Leydig cell numbers were only 7% of control values in the 63-day-old EDS-treated rat. The effect on the testis of EDS treatment administered at a crucial time of testicular development may be explained by withdrawal of androgen; however, the systemic effects indicate non-specific toxicity so any explanation of these changes must be viewed with caution. J. Endocr. (1988) 119, 467–474

scholarly journals Failure of normal adult Leydig cell development in androgen-receptor-deficient mice

2002 ◽  
Vol 115 (17) ◽  
pp. 3491-3496 ◽  
Author(s):  
Peter J. O'Shaughnessy ◽  
Heather Johnston ◽  
Louise Willerton ◽  
Paul J. Baker
Keyword(s):  
Leydig Cell ◽  
Leydig Cells ◽  
Androgen Receptors ◽  
Cell Function ◽  
Adult Population ◽  
Control Level ◽  
Hydroxysteroid Dehydrogenase ◽  
Testicular Development ◽  
Null Mouse ◽  
Mrna Species

During testicular development, fetal and adult populations of Leydig cells arise sequentially. Previous studies have shown that androgen action is required for normal steroidogenic activity in the mouse testis. Therefore, to determine the role of androgens in regulating fetal and adult Leydig cell differentiation and function, Leydig development has been measured in mice lacking functional androgen receptors (AR-null). The Leydig cell number was normal on day 5 after birth in AR-null mice but failed to increase normally thereafter and was about 30% of the control level on day 20 and about 60% of control level in adult animals. Levels of 15 different mRNA species expressed specifically in Leydig cells were measured by real-time PCR in AR-null and control animals. Expression levels of all mRNA species were normal on day 5 when only fetal Leydig cells are present. In older animals, which contain predominantly adult Leydig cells, five of the mRNA species(3β-hydroxysteroid dehydrogenase (3βHSD) type 1, cytochrome P450scc,renin, StAR protein and luteinising hormone receptor) were expressed at normal or increased levels in AR-null mice. All other mRNA species measured showed significantly reduced expression in older animals, and three of these mRNA species (17β-hydroxysteroid dehydrogenase type III, prostaglandin D(PGD)-synthetase and 3βHSD type VI), which are only expressed in the adult population of Leydig cells, were barely detectable in the adult AR-null mouse. The results show that in the absence of androgen receptors, fetal Leydig cell function is normal, but there is a developmental failure of adult Leydig cell maturation, with cells only aquiring partial characteristics of the adult population.

Androgen receptor signalling in testicular Leydig cells is essential for Leydig cell maturation and survival

2014 ◽  
Author(s):  
Laura O'Hara ◽  
Kerry McInnes ◽  
Ioannis Simitsidellis ◽  
Steph Morgan ◽  
Laura Milne ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Leydig Cell ◽  
Leydig Cells ◽  
Cell Maturation ◽  
Receptor Signalling

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

2008 ◽  
Vol 20 (4) ◽  
pp. 505 ◽  
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.

scholarly journals The Leydig Cell MEK/ERK Pathway Is Critical for Maintaining a Functional Population of Adult Leydig Cells and for Fertility

2011 ◽  
Vol 25 (7) ◽  
pp. 1211-1222 ◽  
Author(s):  
Soichi Yamashita ◽  
Ping Tai ◽  
Jean Charron ◽  
CheMyong Ko ◽  
Mario Ascoli
Keyword(s):  
Leydig Cell ◽  
Leydig Cells ◽  
Erk Pathway ◽  
Adult Leydig Cells

A review of drug-induced Leydig cell hyperplasia and neoplasia in the rat and some comparisons with man

1995 ◽  
Vol 14 (7) ◽  
pp. 562-572 ◽  
Author(s):  
DE Prentice ◽  
AW Meikle
Keyword(s):  
Leydig Cell ◽  
Leydig Cells ◽  
Safety Assessment ◽  
Hormonal Status ◽  
Control Mechanisms ◽  
Hormone Production ◽  
Drug Induced ◽  
Cell Hyperplasia ◽  
Etiological Factors ◽  
Func Tion

This paper describes control of normal Leydig cell func tion and testosterone production. The macroscopic and histopathological appearances of spontaneous Leydig cell hyperplasias and tumors (LCT) in the rat are reviewed together with their incidence and hormonal status. Drugs which induce LCTs in chronic studies are discussed and include busereline, carbamazepine, cimetidine, finas teride, flutamide, gemfibrozil, histrelin, hydralazine, indomethacin, isradipine, lactitol, leuprolide, metronida zole, mesulergine, nafarelin, norprolac and vidarabine. The known mechanisms of LCT induction in the rat are reviewed together with other possible etiological factors. The incidence, clinical picture and etiological factors of LCTs in man are also surveyed. Hormone production in Leydig cells and LCTs in rats and man are compared. Differences between the two species are considered, par ticularly with regard to Leydig cell control mechanisms. The paper concludes that drug-induced LCTs in rats are most probably not predictive for man and their occurrence has little relevance in human safety assessment.

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