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PAN2 Maintains mRNA PolyA Tail Homeostasis and Regulates Translation during Spermiogenesis in Mouse

ABSTRACT: Elongation and shortening of the polyA tail are the most common type of post-transcriptional mRNA regulation in eukaryotic cells. Two protein complexes, PAN2-PAN3 and CCR4-NOT, are major cytoplasmic deadenylases that trim the mRNA polyA tails. While PAN2-PAN3 removes the distal portion of the long polyA tails, CCR4-NOT removes adenosine closer to the 3'-UTR. Some subunits in the CCR4-NOT complex have been shown to play synergistic biochemical functions during mouse germ cell development. However, the in vivo functions of the upstream deadenylase PAN2-PAN3 remain unclear, particularly in mammals. In this study, we found that germline-specific deletion of Pan2 leads to male infertility. Pan2 knockout did not affect the prophase of meiosis I, but led to abnormal spermiogenesis and apoptosis of male germ-cells. By Palso-seq and Ribo-lite, we found that the deletion of Pan2 increased the number of long-tail mRNAs in spermiogenesis and disrupted the translation efficiency of genes that should be highly translated at this stage. These findings highlight the crucial physiological functions of PAN2 in gametogenesis and expand our understanding of the posttranscriptional regulation of mRNAs in specific physiological processes.

ORGANISM(S): Mus musculus

PROVIDER: GSE294418 | GEO | 2026/02/06

REPOSITORIES: GEO

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PAN2 Maintains mRNA PolyA Tail Homeostasis and Regulates Translation during Spermiogenesis in Mouse

Project description:PAN2 Maintains mRNA PolyA Tail Homeostasis and Regulates Translation during Spermiogenesis in Mouse

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single-cell sequencing of testis cells from Tex13a-Knockout mice versus wild-type mice

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Expression data from the liver of wild-type and Cnot3+/- mice: Fed vs Fasted

Project description:Decay of mRNAs initiates with shortening of the poly(A) tail. Although the CCR4-NOT complex participates in deadenylation, how it becomes activates remain obscure. We show that complete deficiency in CNOT3, subunit 3 of this complex, is lethal in mice, but that heterozygotes survive as lean mice with hepatic and adipose tissues containing reduced lipid levels. Cnot3+/- mice have enhanced metabolic rates and remain lean on high-fat diets. We further provide evidence suggesting that CNOT3, by changing its level in response to feeding conditions, affects the activity of the CCR4-NOT deadenylase against poly(A) tails of specific mRNAs coding for proteins involved in metabolism of carbohydrates and fats. Because the levels of CNOT3 protein were decreased under fasting conditions and increased upon refeeding and because CNOT3 could be a positive regulator of the CCR4-NOT deadenylase, we hypothesized that the levels of CCR4-NOT target mRNAs would be lower in fed mice than in fasted mice. We compared the gene expression profiles of fed and fasted wild-type mice. Microarray analysis revealed that approximately 1,200 mRNA transcripts were down-regulated in the livers of fed mice. Of these mRNAs, 68 corresponded to the genes up-regulated in the livers of Cnot3+/- mice and fasted wild-type mice. A large number of the 68 identified genes encoded proteins involved in metabolism, especially lipid metabolism and growth. The livers were isolated from 8-week-old fed wild-type, fasted wild-type and fasted Cnot3+/- mice (n = 2 for each genotype).

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