scholarly journals Hspa4l-Deficient Mice Display Increased Incidence of Male Infertility and Hydronephrosis Development

2006 ◽  
Vol 26 (21) ◽  
pp. 8099-8108 ◽  
Author(s):  
Torsten Held ◽  
Ilona Paprotta ◽  
Janchiv Khulan ◽  
Bernhardt Hemmerlein ◽  
Lutz Binder ◽  
...  
Keyword(s):  
Germ Cells ◽  
Sperm Count ◽  
Physiological Role ◽  
Heat Shock Gene ◽  
Seminiferous Tubules ◽  
Genes Encoding ◽  
Null Mutant Mice ◽  
Pachytene Spermatocytes ◽  
Deficient Mice

ABSTRACT The Hspa4l gene, also known as Apg1 or Osp94, belongs to the HSP110 heat shock gene family, which includes three genes encoding highly conserved proteins. This study shows that Hspa4l is expressed ubiquitously and predominantly in the testis. The protein is highly expressed in spermatogenic cells, from late pachytene spermatocytes to postmeiotic spermatids. In the kidney, the protein is restricted to cortical segments of distal tubules. To study the physiological role of this gene in vivo, we generated mice deficient in Hspa4l by gene targeting. Hspa4l-deficient mice were born at expected ratios and appeared healthy. However, approximately 42% of Hspa4l −/− male mice suffered from fertility defects. Whereas the seminiferous tubules of Hspa4l −/− testes contained all stages of germ cells, the number of mature sperm in the epididymis and sperm motility were drastically reduced. The reduction of the sperm count was due to the elimination of a significant number of developing germ cells via apoptosis. No defects in fertility were observed in female mutants. In addition, 12% of null mutant mice developed hydronephrosis. Concentrations of plasma and urine electrolytes in Hspa4l −/− mice were similar to wild-type values, suggesting that the renal function was not impaired. However, Hspa4l −/− animals were preferentially susceptible to osmotic stress. These results provide evidence that Hspa4l is required for normal spermatogenesis and suggest that Hspa4l plays a role in osmotolerance.

Obesity causes weight increases in prepubertal and pubertal male offspring and is related to changes in spermatogenesis and sperm production in rats

2017 ◽  
Vol 29 (4) ◽  
pp. 815 ◽  
Author(s):  
Harish Navya ◽  
Hanumant Narasinhacharya Yajurvedi
Keyword(s):  
Germ Cells ◽  
Sperm Count ◽  
Male Offspring ◽  
Seminiferous Tubules ◽  
Calorie Diet ◽  
Pregnancy And Lactation ◽  
Prepubertal Rats ◽  
Normal Males ◽  
Pachytene Spermatocytes ◽  
Developmental Hierarchy

The effect of obesity on testicular activity in prepubertal and pubertal rats was investigated in the present study. Obesity was induced in adult females by feeding a high-calorie diet (HCD). These females were mated with normal males and were fed an HCD during pregnancy and lactation. The male offspring born to obese mothers and fed an HCD after weaning were found to be obese. Seminiferous tubules of offspring from control mothers (OCM) and offspring from HCD-fed mothers (OHCDM) had the same set of germ cells at different age intervals, namely spermatogonia, leptotene spermatocytes, zygotene spermatocytes, pachytene spermatocytes and round and elongated spermatids on postnatal days (PND) 7, 13, 17, 24 and 36, and on the day of preputial separation, respectively. However, there was a significant decrease in round and elongated spermatids and the epididymal sperm count, coupled with a significant decrease in testosterone and an increase in leptin serum concentrations in OHCDM compared with OCM. These results show that obesity in prepubertal rats does not affect the age-dependent appearance of germ cells according to developmental hierarchy, but it does interfere with spermatid formation, resulting in a reduced sperm count, which may be due to a deficiency of testosterone mediated by hyperleptinaemia.

scholarly journals Involvement of a membrane skeletal protein, 4.1G, for Sertoli/germ cell interaction

Reproduction ◽  
2010 ◽  
Vol 139 (5) ◽  
pp. 883-892 ◽  
Author(s):  
Nobuo Terada ◽  
Nobuhiko Ohno ◽  
Sei Saitoh ◽  
Yurika Saitoh ◽  
Masayuki Komada ◽  
...  
Keyword(s):  
Adhesion Molecule ◽  
Germ Cells ◽  
Cell Membranes ◽  
Cell Interaction ◽  
Seminiferous Tubules ◽  
Wild Type ◽  
Skeletal Protein ◽  
Deficient Mice

We previously reported that a membrane skeletal protein, 4.1G (also known as EPB41L2), is immunolocalized in mouse seminiferous tubules. In this study, the 4.1G immunolocalizaiton was precisely evaluated at various stages of the mouse seminiferous epithelial cycle with ‘in vivocryotechnique’ and also with pre-embedding immunoelectron microscopy in testicular tissues whose ultrastructures were well preserved with glycerol treatment before cryosectioning. In addition, 4.1G-deficient mice were produced, and the morphology of their seminiferous tubules was also evaluated. The 4.1G immunolocalization was different among stages, indicating that it was not only along cell membranes of Sertoli cells, but also those of spermatogonia and early spermatocytes. To confirm the 4.1G immunolocalization in germ cells,in vitroculture of spermatogonial stem cells (SSCs) was used for immunocytochemistry and immunoblotting analysis. In the cultured SSCs, 4.1G was clearly expressed and immunolocalized along cell membranes, especially at mutual attaching regions. In testicular tissues, cell adhesion molecule-1 (CADM1), an intramembranous adhesion molecule, was colocalized on basal parts of the seminiferous tubules and immunoprecipitated with 4.1G in the tissue lysate. Interestingly, in the 4.1G-deficient mice, histological manifestation of the seminiferous tubules was not different from that in wild-type mice, and the CADM1 was also immunolocalized in the same pattern as that in the wild-type. Moreover, the 4.1G-deficient male mice were fertile. These results were probably due to functional redundancy of unknown membrane skeletal molecules in germ cells. Thus, a novel membrane skeletal protein, 4.1G, was found in germ cells, and considering its interaction with CADM family, it probably has roles in attachment of both Sertoli–germ and germ–germ cells.

scholarly journals Mice Lacking the Inhibitory Collagen Receptor LAIR-1 Exhibit a Mild Thrombocytosis and Hyperactive Platelets

2017 ◽  
Vol 37 (5) ◽  
pp. 823-835 ◽  
Author(s):  
Christopher W. Smith ◽  
Steven G. Thomas ◽  
Zaher Raslan ◽  
Pushpa Patel ◽  
Maxwell Byrne ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Kinase Activity ◽  
Thrombus Formation ◽  
Physiological Role ◽  
Src Family Kinase ◽  
Glycoprotein Vi ◽  
Collagen Receptor ◽  
Deficient Mice

Objective— Leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) is a collagen receptor that belongs to the inhibitory immunoreceptor tyrosine-based inhibition motif–containing receptor family. It is an inhibitor of signaling via the immunoreceptor tyrosine-based activation motif–containing collagen receptor complex, glycoprotein VI-FcRγ-chain. It is expressed on hematopoietic cells, including immature megakaryocytes, but is not detectable on platelets. Although the inhibitory function of LAIR-1 has been described in leukocytes, its physiological role in megakaryocytes and in particular in platelet formation has not been explored. In this study, we investigate the role of LAIR-1 in megakaryocyte development and platelet production by generating LAIR-1–deficient mice. Approach and Results— Mice lacking LAIR-1 exhibit a significant increase in platelet counts, a prolonged platelet half-life in vivo, and increased proplatelet formation in vitro. Interestingly, platelets from LAIR-1–deficient mice exhibit an enhanced reactivity to collagen and the glycoprotein VI–specific agonist collagen-related peptide despite not expressing LAIR-1, and mice showed enhanced thrombus formation in the carotid artery after ferric chloride injury. Targeted deletion of LAIR-1 in mice results in an increase in signaling downstream of the glycoprotein VI–FcRγ-chain and integrin αIIbβ3 in megakaryocytes because of enhanced Src family kinase activity. Conclusions— Findings from this study demonstrate that ablation of LAIR-1 in megakaryocytes leads to increased Src family kinase activity and downstream signaling in response to collagen that is transmitted to platelets, rendering them hyper-reactive specifically to agonists that signal through Syk tyrosine kinases, but not to G-protein–coupled receptors.

scholarly journals A novel Amh-Treck transgenic mouse line allows toxin-dependent loss of supporting cells in gonads

Reproduction ◽  
2014 ◽  
Vol 148 (6) ◽  
pp. H1-H9 ◽  
Author(s):  
Mai Shinomura ◽  
Kasane Kishi ◽  
Ayako Tomita ◽  
Miyuri Kawasumi ◽  
Hiromi Kanezashi ◽  
...  
Keyword(s):  
Germ Cells ◽  
Granulosa Cells ◽  
Sertoli Cells ◽  
Seminiferous Tubules ◽  
Specific Cell ◽  
Partial Recovery ◽  
Dependent Manner ◽  
Mouse Line ◽  
Cell Degeneration

Cell ablation technology is useful for studying specific cell lineages in a developing organ in vivo. Herein, we established a novel anti-Müllerian hormone (AMH)-toxin receptor-mediated cell knockout (Treck) mouse line, in which the diphtheria toxin (DT) receptor was specifically activated in Sertoli and granulosa cells in postnatal testes and ovaries respectively. In the postnatal testes of Amh-Treck transgenic (Tg) male mice, DT injection induced a specific loss of the Sertoli cells in a dose-dependent manner, as well as the specific degeneration of granulosa cells in the primary and secondary follicles caused by DT injection in Tg females. In the testes with depletion of Sertoli cell, germ cells appeared to survive for only several days after DT treatment and rapidly underwent cell degeneration, which led to the accumulation of a large amount of cell debris within the seminiferous tubules by day 10 after DT treatment. Transplantation of exogenous healthy Sertoli cells following DT treatment rescued the germ cell loss in the transplantation sites of the seminiferous epithelia, leading to a partial recovery of the spermatogenesis. These results provide not only in vivo evidence of the crucial role of Sertoli cells in the maintenance of germ cells, but also show that the Amh-Treck Tg line is a useful in vivo model of the function of the supporting cell lineage in developing mammalian gonads.

Testicular injection of busulfan for recipient preparation in transplantation of spermatogonial stem cells in mice

2016 ◽  
Vol 28 (12) ◽  
pp. 1916 ◽  
Author(s):  
Yusheng Qin ◽  
Ling Liu ◽  
Yanan He ◽  
Wenzhi Ma ◽  
Huabin Zhu ◽  
...  
Keyword(s):  
Germ Cells ◽  
Fluorescent Protein ◽  
Positive Control ◽  
Negative Control ◽  
Seminiferous Tubules ◽  
Red Fluorescent Protein ◽  
Efferent Duct ◽  
Testicular Injection ◽  
Transplantation Recipient

Intraperitoneal busulfan injections are used to prepare recipients for spermatogonial stem cell (SSC) transplantation but they are associated with haematopoietic toxicity. Testicular injections of busulfan have been proposed to overcome this limitation. To date, testicular injections have not been studied in the mouse model. Therefore, in the present study we used ICR mice as recipients for SSC transplantation and prepared these mice by testicular injection of busulfan on both sides (2, 3, 4 or 6 mg kg–1 per side). Following this, donor germ cells expressing red fluorescent protein (RFP) from transgenic C57BL/6J male mice were transplanted into recipients via the efferent duct on Days 16–17 after busulfan treatment. Positive control mice were prepared by intraperitoneal injection of 40 mg kg–1 busulfan and negative control mice were treated with bilateral testicular injection of 50% dimethyl sulfoxide. On Day 49 after transplantation, recipient mice that were RFP-positive by in vivo imaging were mated with ICR female mice. Donor-derived germ cell colonies with red fluorescence were observed on Day 60 after transplantation, and donor-derived offspring were obtained. The results demonstrated that endogenous germ cells were successfully eliminated in the seminiferous tubules via testicular busulfan administration, and that exogenous SSCs successfully undergo spermatogenesis in the testes of recipient mice prepared by testicular injections of busulfan. In addition to its effects on recipient preparation, this method was safe in rodents and could possibly be adapted for use in other species.

scholarly journals Gab2 deficiency prevents Flt3-ITD driven acute myeloid leukemia in vivo

Leukemia ◽  
2021 ◽  
Author(s):  
Corinna Spohr ◽  
Teresa Poggio ◽  
Geoffroy Andrieux ◽  
Katharina Schönberger ◽  
Nina Cabezas-Wallscheid ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinases ◽  
Myeloid Leukemia ◽  
Downstream Effector ◽  
Flt3 Inhibitor ◽  
Genes Encoding ◽  
Deficient Mice ◽  
Acute Myeloid

AbstractInternal tandem duplications (ITD) of the FMS-like tyrosine kinase 3 (FLT3) predict poor prognosis in acute myeloid leukemia (AML) and often co-exist with inactivating DNMT3A mutations. In vitro studies implicated Grb2-associated binder 2 (GAB2) as FLT3-ITD effector. Utilizing a Flt3-ITD knock-in, Dnmt3a haploinsufficient mouse model, we demonstrate that Gab2 is essential for the development of Flt3-ITD driven AML in vivo, as Gab2 deficient mice displayed prolonged survival, presented with attenuated liver and spleen pathology and reduced blast counts. Furthermore, leukemic bone marrow from Gab2 deficient mice exhibited reduced colony-forming unit capacity and increased FLT3 inhibitor sensitivity. Using transcriptomics, we identify the genes encoding for Axl and the Ret co-receptor Gfra2 as targets of the Flt3-ITD/Gab2/Stat5 axis. We propose a pathomechanism in which Gab2 increases signaling of these receptors by inducing their expression and by serving as downstream effector. Thereby, Gab2 promotes AML aggressiveness and drug resistance as it incorporates these receptor tyrosine kinases into the Flt3-ITD signaling network. Consequently, our data identify GAB2 as a promising biomarker and therapeutic target in human AML.

scholarly journals MFN1 and MFN2 Are Dispensable for Sperm Development and Functions in Mice

2021 ◽  
Vol 22 (24) ◽  
pp. 13507
Author(s):  
Junru Miao ◽  
Wei Chen ◽  
Pengxiang Wang ◽  
Xin Zhang ◽  
Lei Wang ◽  
...  
Keyword(s):  
Germ Cells ◽  
Knockout Mice ◽  
Seminiferous Tubules ◽  
Wild Type ◽  
Double Knockout ◽  
Wild Type Littermate ◽  
Mitofusin 2 ◽  
Sperm Development ◽  
Mitofusin 1 ◽  
Deficient Mice

MFN1 (Mitofusin 1) and MFN2 (Mitofusin 2) are GTPases essential for mitochondrial fusion. Published studies revealed crucial roles of both Mitofusins during embryonic development. Despite the unique mitochondrial organization in sperm flagella, the biological requirement in sperm development and functions remain undefined. Here, using sperm-specific Cre drivers, we show that either Mfn1 or Mfn2 knockout in haploid germ cells does not affect male fertility. The Mfn1 and Mfn2 double knockout mice were further analyzed. We found no differences in testis morphology and weight between Mfn-deficient mice and their wild-type littermate controls. Spermatogenesis was normal in Mfn double knockout mice, in which properly developed TRA98+ germ cells, SYCP3+ spermatocytes, and TNP1+ spermatids/spermatozoa were detected in seminiferous tubules, indicating that sperm formation was not disrupted upon MFN deficiency. Collectively, our findings reveal that both MFN1 and MFN2 are dispensable for sperm development and functions in mice.

scholarly journals Autologous transplantation of spermatogonial stem cells restores fertility in congenitally infertile mice

2020 ◽  
Vol 117 (14) ◽  
pp. 7837-7844
Author(s):  
Mito Kanatsu-Shinohara ◽  
Narumi Ogonuki ◽  
Shogo Matoba ◽  
Atsuo Ogura ◽  
Takashi Shinohara
Keyword(s):  
Stem Cells ◽  
Sertoli Cells ◽  
Expression Patterns ◽  
Autologous Transplantation ◽  
Spermatogonial Stem Cells ◽  
Congenital Defects ◽  
Seminiferous Tubules ◽  
Special Environment ◽  
Deficient Mice

The blood–testis barrier (BTB) is thought to be indispensable for spermatogenesis because it creates a special environment for meiosis and protects haploid cells from the immune system. The BTB divides the seminiferous tubules into the adluminal and basal compartments. Spermatogonial stem cells (SSCs) have a unique ability to transmigrate from the adluminal compartment to the basal compartment through the BTB upon transplantation into the seminiferous tubule. Here, we analyzed the role ofCldn11, a major component of the BTB, in spermatogenesis using spermatogonial transplantation.Cldn11-deficient mice are infertile due to the cessation of spermatogenesis at the spermatocyte stage.Cldn11-deficient SSCs failed to colonize wild-type testes efficiently, andCldn11-deficient SSCs that underwent double depletion ofCldn3andCldn5showed minimal colonization, suggesting that claudins on SSCs are necessary for transmigration. However,Cldn11-deficient Sertoli cells increased SSC homing efficiency by >3-fold, suggesting that CLDN11 in Sertoli cells inhibits transmigration of SSCs through the BTB. In contrast to endogenous SSCs in intactCldn11-deficient testes, those from WT orCldn11-deficient testes regenerated sperm inCldn11-deficient testes. The success of this autologous transplantation appears to depend on removal of endogenous germ cells for recipient preparation, which reprogrammed claudin expression patterns in Sertoli cells. Consistent with this idea, in vivo depletion ofCldn3/5regenerated endogenous spermatogenesis inCldn11-deficient mice. Thus, coordinated claudin expression in both SSCs and Sertoli cells expression is necessary for SSC homing and regeneration of spermatogenesis, and autologous stem cell transplantation can rescue congenital defects of a self-renewing tissue.

Differentiation of germ cells in seminiferous tubules transplanted to testes of germ cell-deficient mice ofW/Wv andSI/SId genotypes

1989 ◽  
Vol 139 (2) ◽  
pp. 329-334 ◽  
Author(s):  
Hideya Kuroda ◽  
Hiroki Nakayama ◽  
Mikio Namiki ◽  
Keishi Matsumoto ◽  
Yoshitake Nishimune ◽  
...  
Keyword(s):  
Germ Cell ◽  
Germ Cells ◽  
Seminiferous Tubules ◽  
Deficient Mice

scholarly journals In vivo regulation of AT1a receptor-mediated intracellular uptake of [125I]Val5-ANG II in the kidneys and adrenals of AT1a receptor-deficient mice

2008 ◽  
Vol 294 (2) ◽  
pp. F293-F302 ◽  
Author(s):  
Xiao C. Li ◽  
Jia L. Zhuo
Keyword(s):  
Adrenal Glands ◽  
Physiological Role ◽  
Intracellular Uptake ◽  
Ang Ii ◽  
Angiotensin Receptor ◽  
Wild Type ◽  
In Vivo Autoradiography ◽  
At1a Receptor ◽  
Deficient Mice

Using type 1a angiotensin receptor (AT1a) receptor-deficient (Agtr1a−/−) mice and in vivo autoradiography, we tested the hypothesis that intracellular uptake of ANG II in the kidney and adrenal glands is primarily mediated by AT1a receptors and that the response is regulated by prevailing endogenous ANG II. After pretreatment of wild-type (Agtr1a+/+) and Agtr1a−/− mice ( n = 6–9 each group) with or without captopril (25 mg·kg−1·day−1) or losartan (10 mg·kg−1·day−1) for 2 wk, [125I]Val5-ANG II was infused for 60 min. Intracellular uptake of [125I]Val5-ANG II was determined by quantitative in vivo autoradiography after washout of circulating [125I]Val5-ANG II. Basal intracellular ANG II levels were 65% lower in the kidney ( P < 0.001), but plasma ANG II levels were threefold higher, in Agtr1a−/− than wild-type mice ( P < 0.01). Although plasma [125I]Val5-ANG II levels were similar, urinary excretion of [125I]Val5-ANG II was fourfold higher in Agtr1a−/− mice ( P < 0.001). By contrast, intracellular [125I]Val5-ANG II levels were ∼80% lower in the kidney and adrenal glands of Agtr1a−/− mice ( P < 0.01). Captopril decreased endogenous plasma and renal ANG II levels ( P < 0.01) but increased intracellular uptake of [125I]Val5-ANG II in the kidney and adrenal glands of wild-type and Agtr1a−/− mice ( P < 0.01). Losartan largely blocked renal and adrenal uptake of [125I]Val5-ANG II in wild-type and Agtr1a−/− mice. Thus 80% of intracellular ANG II uptake in the kidney and adrenal glands is mediated by AT1a receptors, whereas AT1b receptor- and other non-receptor-mediated mechanisms account for 20% of the response. Our results suggest that AT1a receptor-mediated uptake of extracellular ANG II may play a physiological role in the kidney and adrenal glands.

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