Apoptosis in male germ cells in response to cyclin A1-deficiency and cell cycle arrest

Salazar, Glicella; Liu, Dong; Liao, Ching Lung; Batkiewicz, Leah; Arbing, Rachel; Chung, Sydney S.C.; Lele, Karen M.; Wolgemuth, Debra J.

doi:10.1016/s0006-2952(03)00513-6

Cited by 23 publications

(16 citation statements)

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“…One of the features of the Ccna1 Ϫ/Ϫ phenotype was that arrested late-pachytene to diplotene spermatocytes underwent apoptosis. The induction of an apparent apoptotic response (TUNEL-positive) has been seen in various other gene knockout studies that resulted in impaired meiosis, such as A-myb (Toscani et al, 1997), Hsp 70.2 (Dix et al, 1997), Mlh1 (Edelmann et al, 1996), Spo11 (Baudat et al, 2000;Romanienko and Camerini-Otero, 2000), Atm (Xu et al, 1996), and so on (reviewed in Salazar et al, 2003). It would appear that the induction of cell death is critical for ensuring not only that the proper number of germ cells is produced during normal spermatogenesis but also that gametes that have not gone through meiosis properly are not formed.…”

Section: Discussionmentioning

confidence: 96%

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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Section: Discussionmentioning

confidence: 96%

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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“…Deficiency of cyclin E2 [ID: T1-151] leads to apoptosis of spermatocytes during meiotic division, but half the mice are still fertile (Geng et al, 2003). Cyclin A1 [ID: T1-19] is extensively expressed in germ cells, and its absence leads to meiotic arrest and increased germ cells apoptosis in diplotene/diakinesis spermatocytes as well as desynapsis abnormalities, apoptosis, and sterility (Liu et al, 1998;Salazar et al, 2003;Wolgemuth et al, 2004). A CDK inhibitor 1C (p57kip2) [ID: T1-152] blocks the cell cycle by acting on multiple cyclin-CDK complexes.…”

Section: List Of Genes/proteins Present At High Levels In Spermatocytmentioning

confidence: 99%

Surfing the wave, cycle, life history, and genes/proteins expressed by testicular germ cells. Part 1: Background to spermatogenesis, spermatogonia, and spermatocytes

Hermo

Pelletier

Cyr

et al. 2009

Microscopy Res & Technique

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As germ cells divide and differentiate from spermatogonia to spermatozoa, they share a number of structural and functional features that are common to all generations of germ cells and these features are discussed herein. Germ cells are linked to one another by large intercellular bridges which serve to move molecules and even large organelles from the cytoplasm of one cell to another. Mitochondria take on different shapes and features and topographical arrangements to accommodate their specific needs during spermatogenesis. The nuclear envelope and pore complex also undergo extensive modifications concomitant with the development of germ cell generations. Apoptosis is an event that is normally triggered by germ cells and involves many proteins. It occurs to limit the germ cell pool and acts as a quality control mechanism. The ubiquitin pathway comprises enzymes that ubiquitinate as well as deubiquitinate target proteins and this pathway is present and functional in germ cells. Germ cells express many proteins involved in water balance and pH control as well as voltage-gated ion channel movement. In the nucleus, proteins undergo epigenetic modifications which include methylation, acetylation, and phosphorylation, with each of these modifications signaling changes in chromatin structure. Germ cells contain specialized transcription complexes that coordinate the differentiation program of spermatogenesis, and there are many male germ cell-specific differences in the components of this machinery. All of the above features of germ cells will be discussed along with the specific proteins/genes and abnormalities to fertility related to each topic.

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“…A robust apoptotic response has been reported in a number of mutant strains of mice that exhibit impaired fertility or sterility (Salazar et al, 2003). We therefore performed in situ terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling (TUNEL) assays on histological sections of control and mutant testes of different ages (3 weeks, 2 months, 6 months and 1 year of age) to detect DNA fragmentation.…”

Section: Research Articlementioning

confidence: 99%

The first bromodomain of Brdt, a testis-specific member of the BET sub-family of double-bromodomain-containing proteins, is essential for male germ cell differentiation

et al. 2007

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*Brdt is a testis-specific member of the distinctive BET sub-family of bromodomain motif-containing proteins, a motif that binds acetylated lysines and is implicated in chromatin remodeling. Its expression is restricted to the germ line, specifically to pachytene and diplotene spermatocytes and early spermatids. Targeted mutagenesis was used to generate mice carrying a mutant allele of Brdt, Brdt ⌬BD1, which lacks only the first of the two bromodomains that uniquely characterize BET proteins. Homozygous Brdt ⌬BD1/⌬BD1 mice were viable but males were sterile, producing fewer and morphologically abnormal sperm. Aberrant morphogenesis was first detected in step 9 elongating spermatids, and those elongated spermatids that were formed lacked the distinctive foci of heterochromatin at the peri-nuclear envelope. Quantitative reverse transcription (RT)-PCR showed threefold increased levels of histone H1t (Hist1h1t) in Brdt ⌬BD1/⌬BD1 testes and chromatin immunoprecipitation revealed that Brdt protein, but not Brdt ⌬BD1 protein, was associated with the promoter of H1t. Intracytoplasmic sperm injection suggested that the DNA in the Brdt ⌬BD1 mutant sperm could support early embryonic development and yield functional embryonic stem cells. This is the first demonstration that deletion of just one of the two bromodomains in members of the BET sub-family of bromodomain-containing proteins has profound effects on in vivo differentiation.

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Apoptosis in male germ cells in response to cyclin A1-deficiency and cell cycle arrest

Cited by 23 publications

References 91 publications

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

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

Surfing the wave, cycle, life history, and genes/proteins expressed by testicular germ cells. Part 1: Background to spermatogenesis, spermatogonia, and spermatocytes

The first bromodomain of Brdt, a testis-specific member of the BET sub-family of double-bromodomain-containing proteins, is essential for male germ cell differentiation

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