Proliferation and Differentiation of Spermatogonial Stem Cells in the W/Wv Mutant Mouse Testis1

Ohta, Hiroshi; Tohda, Akira; Nishimune, Yoshitake

doi:10.1095/biolreprod.103.019323

Cited by 99 publications

(74 citation statements)

References 36 publications

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“…Coupling the present data with previous observations of spermatogonial morphology in these testes, we now understand that c-Kit protein expression occurs only when differentiating spermatogonia emerge in the testes of irradiated rats treated with the GnRH antagonist for 4 weeks and more (Shuttlesworth et al 2000). In a study of W/W v mutant mice, which produce non-functional c-Kit receptor protein, spermatogonia expressing c-Kit are present in 2-week-old W/W v mutant mice but are absent in 10-week-old animals (Ohta et al 2003). Administration of a GNRH antagonist for 4 weeks to reduce intratesticular testosterone in 10-week-old W/W v mice resulted in the emergence of c-Kit-positive spermatogonia.…”

Section: Discussionmentioning

confidence: 99%

Expression of c-Kit receptor mRNA and protein in the developing, adult and irradiated rodent testis

Prabhu¹,

Meistrich²,

McLaughlin³

et al. 2006

Reproduction

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Germ cell proliferation, migration and survival during all stages of spermatogenesis are affected by stem cell factor signalling through the c-Kit receptor, the expression and function of which are vital for normal male reproductive function. The present study comprehensively describes the c-Kit mRNA and protein cellular expression profiles in germ cells of the postnatal and adult rodent testis, revealing their significant elevation in synthesis at the onset of spermatogenesis. Real-time PCR analysis for both mice and rats matched the cellular mRNA expression profile where examined. Localization studies in normal mouse testes indicated that both c-Kit mRNA and protein are first detectable in differentiating spermatogonia. In addition, all spermatogonia isolated from 8-day-old mice displayed detectable c-Kit mRNA, but 30 -50% of these lacked protein expression. The c-Kit mRNA and protein profile in normal rat testes indicated expression in gonocytes, in addition to differentiating spermatogonia. However, in the irradiated adult rat testes, in which undifferentiated spermatogonia are the only germ cell type, mRNA was also detected in the absence of protein. This persisted at 3 days and 1 and 2 weeks following treatment with gonadotrophin-releasing hormone (GnRH) antagonist to stimulate spermatogenesis recovery. By 4 weeks of GnRH antagonist treatment, accompanying the emergence of differentiating spermatogonia, both mRNA and protein were detected. Based on these observations, we propose that c-Kit mRNA and protein synthesis are regulated separately, possibly by influences linked to testis maturation and circulating hormone levels.

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Section: Discussionmentioning

confidence: 99%

Expression of c-Kit receptor mRNA and protein in the developing, adult and irradiated rodent testis

Prabhu¹,

Meistrich²,

McLaughlin³

et al. 2006

Reproduction

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“…6A and B, SCF triggered the activation of c-kit in both cell types, as demonstrated by an increase in the phospho-c-kit signal, and this consequently resulted in the phosphorylation of Erk. The SCF-c-kit pathway is well known as a promoter of migration in different types of stem cells such as hematopoietic (Hassan and Zander, 1996 for review), spermatogonial (Ohta et al, 2003) and neural stem cells (Jin et al, 2002;Erlandsson et al, 2004;Sun et al, 2004). We therefore examined the possibility that the activation of the c-kit pathway led to a similar functional effect, in addition to the increased kinase activity detected biochemically.…”

Section: Involvement Of the Stem Cell Factormentioning

confidence: 99%

Stem cell factor and mesenchymal and neural stem cell transplantation in a rat model of Huntington's disease

Bantubungi

Blum

Cuvelier

et al. 2008

Molecular and Cellular Neuroscience

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Neural and mesenchymal stem cells have been proposed as alternative sources of cells for transplantation into the brain in neurodegenerative disorders. However, the endogenous factors controlling their engraftment within the injured parenchyma remain ill-defined. Here, we demonstrate significant engraftment of undifferentiated exogenous mesenchymal or neural stem cells throughout the lesioned area in a rat model for Huntington's disease, as late as 8 weeks post-transplantation. We show that stem cell factor (SCF), strongly up-regulated within host cells in the damaged striatum, is able to activate the SCF receptor c-kit and its signaling pathway and to promote the migration and proliferation of mesenchymal and neural stem cells in vitro. Furthermore, c-kit receptor blockade alters neural stem cell distribution within the lesioned striatum. Host SCF expression is observed in atypical cells expressing glial fibrillary acidic protein and doublecortin in the lesioned striatum and in migrating doublecortin-positive progenitors. Taken together, these data demonstrate that SCF produced in situ in the lesioned striatum is an important factor in promoting the engraftment of stem cells within the lesioned brain.

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“…To confirm the germ-line potential of the mutated GS cells, eight clones, which included seven randomly chosen trapped clones (clone 6, 7, 13, 14, 27, 30, and 39) and one of targeted clones (clone 101), were microinjected into the seminiferous tubules of three to nine infertile WBB6F1-W͞W v (W) mice. Because the germ cells of W mice are unable to differentiate beyond the spermatogonium stage owing to mutations in the c-kit gene, spermatogenesis in the recipient testis must originate from transplanted cells (22). After transplantation, the testes grew significantly (Fig.…”

Section: Mutagenesis Of Gs Cellsmentioning

confidence: 99%

Production of knockout mice by random or targeted mutagenesis in spermatogonial stem cells

Kanatsu-Shinohara

Ikawa

Takehashi

et al. 2006

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

146

108

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Stem cells represent a unique population of cells with self-renewal capacity. Although they are important therapeutic targets, the genetic manipulation of tissue-specific stem cells has been limited, which complicates the study and practical application of these cells. Here, we demonstrate successful gene trapping and homologous recombination in spermatogonial stem cells. Cultured spermatogonial stem cells were transfected with gene trap or gene targeting vectors. Mutagenized stem cells were expanded clonally by drug selection. These cells underwent spermatogenesis and produced heterozygous offspring after transplantation into the seminiferous tubules of infertile mouse testes. Heterozygous mutant mice were intercrossed to produce homozygous gene knockouts. Using this strategy, the efficiency of homologous recombination for the occludin gene locus was 1.7% using a nonisogenic DNA construct. These results demonstrate the feasibility of altering genes in tissue-specific stem cells in a manner similar to embryonic stem cells and have important implications for gene therapy and animal transgenesis.spermatogenesis ͉ germ cell ͉ testis ͉ transplantation S tem cells represent a unique cell population with self-renewal potential (1). Although stem cells are low in number, these cells proliferate extensively to sustain the various self-renewing tissues, such as bone marrow and intestine. Although these tissue-specific stem cells normally divide very slowly, stem cells are the last cell type to be destroyed after cytotoxic damage, and they regenerate the entire tissue in a relatively short time. In addition, stem cells often have migratory activities, and they can be transplanted between animals; transplanted stem cells migrate to a specific niche and regenerate the self-renewing tissue. Because of their unique properties, stem cells have become the attractive target of cell and gene therapies.Among the many types of tissue-specific stem cells, spermatogonial stem cells are unique in that they have germ-line potential (2, 3). Genetic modification of spermatogonial stem cells creates permanent changes in the germ line, which are transmitted to the offspring by means of fertilization. In contrast to female germ-line cells, which cease to divide after birth, male germ-line cells proliferate continuously and produce sperm throughout the life of the animal. If these stem cells could be cultured and manipulated in a manner similar to embryonic stem (ES) cells (4, 5), they could be used to create knockout animals. As a first step toward this goal, a germ cell transplantation technique was developed in 1994 (6, 7), in which dissociated donor testis cells colonized the seminiferous tubules of infertile recipient testis and produced donor-derived spermatogenesis and offspring. Although this technique was an opportunity to produce offspring from manipulated spermatogonial stem cells, it has been difficult to produce transgenic animals using spermatogonial stem cells, because their number is very low in the testis, and the lack of me...

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Proliferation and Differentiation of Spermatogonial Stem Cells in the W/Wv Mutant Mouse Testis1

Cited by 99 publications

References 36 publications

Expression of c-Kit receptor mRNA and protein in the developing, adult and irradiated rodent testis

Expression of c-Kit receptor mRNA and protein in the developing, adult and irradiated rodent testis

Stem cell factor and mesenchymal and neural stem cell transplantation in a rat model of Huntington's disease

Production of knockout mice by random or targeted mutagenesis in spermatogonial stem cells

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