Mice lacking cyclin‐dependent kinase inhibitor p19^Ink4d show strain‐specific effects on male reproduction

Abstract

p19(Ink4d) is a member of the INK4 family of cyclin-dependent kinase inhibitors, which are important negative regulators of the G1-phase cyclin-dependent kinases CDK4 and CDK6. On a mixed C57BL/6 x 129P2/OlaHsd background, mice deficient for p19(Ink4d) exhibited defects in male reproductive function including testicular atrophy, alteration in serum follicle stimulating hormone, qualitative increase in germ cell apoptosis, and delayed kinetics of meiotic prophase markers (Zindy et al., 2001. Mol Cell Biol 21:3244-3255; Zindy et al., 2000. Mol Cell Biol 20:372-378). In this study, a quantitative assessment of these aspects of reproductive capacity demonstrated relatively mild deficits in p19(Ink4d-/-) males compared to controls. These effects did not dramatically worsen in older males although some seminiferous tubule defects were observed. Following marker-assisted backcrossing into the C57BL/6 background, p19(Ink4d-/-) males did not display defects in testis weights, sperm numbers, serum FSH, germ cell apoptosis, or kinetics of selected meiotic prophase markers. These studies indicate that a reduction in Ink4 family function by the loss of p19(Ink4d) is sufficient to induce mild reproductive defects in male mice with a mixed genetic background, but not in the C57BL/6 genetic background.

p19Ink4d Is a Tumor Suppressor and Controls Pituitary Anterior Lobe Cell Proliferation

“…4A). Though the testes of p19 Ϫ/Ϫ male mice were slightly smaller than those of WT mice, p19-deficient males were fertile, which is in agreement with previous findings (27,28,40). After monitoring a cohort of 24 p19 Ϫ/Ϫ , 9 p19 ϩ/Ϫ , and 15 wild-type mice for 27 months, we found that 14 (58.3%) p19 Ϫ/Ϫ and 3 (30%) p19 ϩ/Ϫ mice spontaneously developed tumors, whereas only 2 (13.3%) WT mice displayed tumors at a similar age ( Fig.…”

“…p19 is highly and ubiquitously expressed in both fetal and adult tissues (24), and loss or downregulation of p19 is frequently detected in human hepatocellular carcinoma (25), testicular germ cell tumors (26), glioblastoma, leukemia, and lung adenocarcinoma (Oncomine TCGA data set; https://www .oncomine.org/resource/). Paradoxically, disruption of p19 in mice by insertion of a LacZ-Neo cassette into exon 2 results in a relatively minor phenotype of testicular atrophy with no tumor development (27,28). The pituitary gland is a central endocrine organ that controls growth, reproduction, and metabolism.…”

Loss of Bmyc results in increased apoptosis associated with upregulation of Myc expression in juvenile murine testis

“…Ink4d KO mice studied, two displayed atrophied seminiferous tubules (Buchold et al 2007). Unfortunately, the authors did not measure Cdk4 expression levels.…”

Computational analysis of the transcriptional regulation of the adenine nucleotide translocator isoform 4 gene and its role in spermatozoid glycolytic metabolism

“…The ANT4 protein is known to be specifically expressed during spermatogenesis and our results provide a first validation to our computational analysis of promoter sequences: several genes involved in spermatogenesis share with the ANT4 gene particular strings in their promoter and some of these strings (matrices from the V$EBOX and V$HIFF families) are known to be specifically involved in the glycolytic pathway. The last identified genes encode for proteins with different functions: cell cycle progression (CDK4, (Buchold et al, 2007)), cell growth (IGF2BP3 and IGF2R, (Nielsen et al, 1999)), or meiosis (RMND1) which could be associated with spermatogenesis. The presence of the previously proposed E2F6-binding element (Kehoe et al, 2008), which is found in the promoters of genes involved in mouse meiosis, was not used in our analysis: This E2F6-binding element is localised downstream the two proposed transcription start sites in positions 128 651 532 (EnsEMBL) and 128 651 555 (Eldorado) and thus could not be considered as a valid regulatory sequence.…”