Developmental regulation of the bcl-2 family during spermatogenesis: Insights into the sterility of bcl-w−/− male mice

Meehan, Terri Ann; Loveland, Kate L; Kretser, D. M. De; Cory, Suzanne; Print, Cristin G.

doi:10.1038/sj.cdd.4400799

Cited by 44 publications

(38 citation statements)

References 41 publications

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“…Partially overlapping Smad6 and Smad7 expression in adult spermatogonia and spermatocytes, and the extension of Smad7 expression into spermatids, further indicates there is precise regulation of TGF␤ signaling inhibition. Hence, transcription of SMAD genes is independently regulated and differs between the first wave of spermatogenesis and the cycling of the adult seminiferous epithelium, a concept we have reported for Bcl2 family members (Meehan et al, 2001). The restricted germ cell production of Smad8 in the adult mouse testis suggests a specific requirement for SMAD8-mediated signal transduction in adult somatic cells and spermatogonia.…”

Section: Discussionmentioning

confidence: 69%

SMAD expression in the testis: An insight into BMP regulation of spermatogenesis

Itman

Loveland

2007

Developmental Dynamics

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Bone morphogenetic proteins (BMPs), members of the transforming growth factor-␤ superfamily, extensively influence events that establish male fertility, affecting germ cells and somatic cells throughout fetal and postnatal life. BMP signals are relayed by SMAD proteins, transcription factors that translocate to the nucleus upon ligand stimulation. We show that BMP signaling in the testis may be regulated by selective expression of BMP-responsive and inhibitory SMADs, with expression differing between the first wave and adult spermatogenesis. Smad1, Smad5, Smad8, Smad4, Smad6, and Smad7 expression is ubiquitous during testis development but becomes cell-specific in the adult. Furthermore, regulated SMAD6 protein expression at the onset of spermatogenesis suggests differential responsiveness of spermatogonial subpopulations to ligands. In vitro, immature Sertoli cells and spermatogonia transduce BMP2 and BMP4 signals by means of SMAD1, SMAD5, and SMAD8. Based on these findings, we extrapolate these data to interpret BMP mutant testis phenotypes in terms of SMAD availability for signal transduction. Developmental Dynamics 237:97-111, 2008.

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Section: Discussionmentioning

confidence: 69%

SMAD expression in the testis: An insight into BMP regulation of spermatogenesis

Itman

Loveland

2007

Developmental Dynamics

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“…Some proteins of the cellintrinsic pathway, the Bcl-2 family of proteins, are essential for normal spermatogenesis. The expression of Bax, a pro-apoptotic protein, peaks during the time of the massive germ cell death observed at day 22 during postnatal development of the testis in mice (Rodriguez et al, 1997) and is still expressed in pachytene spermatocytes in the adults (Yan et al, 2000;Meehan et al, 2001). In testes of Baxdeficient mice, there was an accumulation of spermatogonia, a phenotype consistent with the failure of germ cell death during the first wave of spermatogenesis (Knudson et al, 1995).…”

Section: Discussionmentioning

confidence: 70%

Induction of apoptosis involving multiple pathways is a primary response to cyclin A1‐deficiency in male meiosis

Salazar

Joshi

Liu

et al. 2005

Developmental Dynamics

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The meiotic arrest in male mice null for the cyclin A1 gene (Ccna1) was associated with apoptosis of spermatocytes. To determine whether the apoptosis in spermatocytes was triggered in response to the arrest at G2/M phase, as opposed to being a secondary response to overall disruption of spermatogenesis, we examined testes during the first wave of spermatogenesis by terminal deoxynucleotidyl transferase-mediated deoxyuridinetriphosphate nick end-labeling (TUNEL) staining. We observed enhanced apoptosis coinciding with the arrest point in postnatal day 22 tubules, with no overt degeneration. Along with activation of caspase-3, an increase in the levels and change of subcellular localization of Bax protein was observed in cyclin A1-deficient spermatocytes, which coincided with the detection of apoptosis. As p53 is implicated in the activation of Bax-mediated cell death, we generated mice lacking both cyclin A1 and p53. Although the absence of p53 did not rescue the meiotic arrest, there was a decrease in the number of apoptotic cells in the double-mutant testes. This finding suggested that p53 may be involved in the process by which the arrested germ cells are removed from the seminiferous tubules but that other pathways function as well to ensure removal of the arrested spermatocytes. Developmental Dynamics 234:114 -123, 2005.

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“…Age dependent changes in cell survival resulting from FSH suppression may be due to developmentally regulated changes in the cellular synthesis of apoptotic regulators, such that documented for members of the Bcl-2 family during the first wave of mouse spermatogenesis (Meehan et al 2001). The Bcl-w (Yan et al 2000) and Bok ) mRNAs were shown to be up-and down-regulated respectively by FSH in vitro, and the bcl-w knockout mouse has elevated germ cell apoptosis following 14 dpp, indicating the potential influence of Bcl-2 family members on the cellular responses in this model.…”

Section: Germ Cell Developmentmentioning

confidence: 99%

“…FSH-regulated apoptosis during the first spermatogenic wave has not been examined, however in adult rats, germ cells are lost through apoptosis (Meachem et al 1999), rather than through reduced proliferation when FSH is manipulated (McLachlan et al 1995). However the regulation of adult spermatogenesis cannot be assumed to be mediated in the same manner as is the first spermatogenic wave, as shifts in the expression patterns of key regulatory genes (i.e., Bcl-2 family members and stem cell factor (SCF) have been observed as Sertoli cells mature and eventually mature germ cell populations emerge (Munsie et al 1997, Huang et al 1992, Meehan et al 2001.…”

Section: Introductionmentioning

confidence: 99%

Developmentally distinct in vivo effects of FSH on proliferation and apoptosis during testis maturation

Meachem¹,

Ruwanpura²,

Ziolkowski³

et al. 2005

Journal of Endocrinology

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The critical influence of follicle stimulating hormone (FSH) on male fertility relates both to its impact on Sertoli cell proliferation in perinatal life and to its influence on the synthesis of Sertoli cell-derived products essential for germ cell survival and function in the developing adult testis. The nature and timing of this shift of germ cells to their reliance on specific Sertoli cell-derived products are not defined. Based on existing data, it is apparent that the dominant function of FSH shifts between 9 and 18 day postpartum (dpp) during the first wave of spermatogenesis from driving Sertoli cell proliferation to support germ cells. To enable comprehensive analysis of the impact of acute in vivo FSH suppression on Sertoli and germ cell development, FSH was selectively suppressed in Sprague-Dawley rats by passive immunisation for 2 days and/or 4 days prior to testis collection at 3, 9 and 18 dpp. The 3 dpp samples displayed no measurable changes, while 4 days of FSH suppression decreased Sertoli cell proliferation and numbers in 9 dpp, but not 18 dpp, animals. In contrast, germ cell numbers were unaffected at 9 dpp but decreased at 18 dpp following FSH suppression, with a corresponding increase in germ cell apoptosis measured at 18 dpp. Sixty transcripts were measured as changed at 18 dpp in response to 4 days of FSH suppression, as assessed using Affymetrix microarrays. Some of these are known as Sertoli cell-derived FSH-responsive genes (e.g. StAR, cathepsin L, insulin-like growth factor binding protein-3), while others encode proteins involved in cell cycle and survival regulation (e.g. cyclin D1, scavenger receptor class B 1). These data demonstrate that FSH differentially affects Sertoli and germ cells in an age-dependent manner in vivo, promoting Sertoli cell mitosis at day 9, and supporting germ cell viability at day 18. This model has enabled identification of candidate genes that contribute to the FSH-mediated pathway by which Sertoli cells support germ cells.

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Developmental regulation of the bcl-2 family during spermatogenesis: Insights into the sterility of bcl-w−/− male mice

Cited by 44 publications

References 41 publications

SMAD expression in the testis: An insight into BMP regulation of spermatogenesis

SMAD expression in the testis: An insight into BMP regulation of spermatogenesis

Induction of apoptosis involving multiple pathways is a primary response to cyclin A1‐deficiency in male meiosis

Developmentally distinct in vivo effects of FSH on proliferation and apoptosis during testis maturation

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