Cyclin A1-deficient mice lack histone H3 serine 10 phosphorylation and exhibit altered aurora B dynamics in late prophase of male meiosis

Abstract

Male mice lacking cyclin A1 protein are sterile. Their sterility results from an arrest in the meiotic cell cycle of spermatocytes, which we now identify as occurring at late diplotene, immediately before diakinesis. The stage of arrest in cyclin A1-deficient mice is distinct from the arrest seen in spermatocytes that are deficient in its putative catalytic partner Cdk2, which occurs much earlier in pachytene. The arrest in cyclin A1-deficient spermatocytes is also accompanied by an unusual clustering of centromeric heterochromatin. Consistent with a possible defect in the centromeric region, immunofluorescent staining of cyclin A1 protein shows localization in the region of the centromere. Phosphorylation of histone H3 at serine 10 in pericentromeric heterochromatin, which normally occurs in late diplotene, is reduced in spermatocytes from heterozygous Ccna1(+/-) testes and completely absent in spermatocytes with no cyclin A1 protein. Concomitantly, the levels of pericentromeric aurora B kinase, known to phosphorylate histone H3 during meiosis, are partially reduced in spermatocytes from testes of heterozygous mice and further reduced in homozygous null spermatocytes. These data suggest a critical and concentration-dependent function for cyclin A1 in the pericentromeric region in late diplotene of meiosis, perhaps in assembly or function of the passenger protein complex.

DAZAP1, an hnRNP protein, is required for normal growth and spermatogenesis in mice

“…Fn/Fn mutants resemble those of the Ccna1-null mutants (Liu et al 1998;Nickerson et al 2007). Ccna1 encodes cyclin A1, a member of the cyclin family that regulates cell cycle progression.…”

CDK2 is required for proper homologous pairing, recombination and sex-body formation during male mouse meiosis

“…The identity of the protein or proteins acting as partners of CDK2 in these different processes is not known. During mouse meiosis, cyclin A1, a putative catalytic partner of CDK2 appears at centromeres and, unlike Cdk2 -/-spermatocytes, those of cyclin A1-deficient mice arrest at late diplotene (Nickerson et al, 2007). Thus, we suggest that another type of CDK2-binding cyclin (such as cyclin E or cyclin B3) or a CDK2 non-cyclin activator (such as one of the RINGO protein family members) might act as the catalytic partner of CDK2 during early meiotic prophase.…”

Cyclin-A1 represents a new immunogenic targetable antigen expressed in acute myeloid leukemia stem cells with characteristics of a cancer-testis antigen

“…16,17 CCNA1 Ϫ/Ϫ mice are viable and phenotypically normal, with the exception of male infertility. 18,19 Cyclin-A1 is aberrantly expressed in AML as well as other Submitted July 7, 2011; accepted February 4, 2012. Prepublished online as Blood First Edition paper, April 23, 2012; DOI 10.1182 DOI 10.…”

“…16,17 CCNA1 Ϫ/Ϫ mice are viable and phenotypically normal, with the exception of male infertility. 18,19 Cyclin-A1 is aberrantly expressed in AML as well as other malignancies. 16,20 In AML, it can sustain the malignant phenotype through pro-proliferative and antiapoptotic activities, [21][22][23] and overexpression of cyclin-A1 in mice causes dysplastic myelopoiesis with 15% of mice developing transplantable myeloid leukemias.…”