Genetic loss of importin α4 causes abnormal sperm morphology and impacts on male fertility in mouse

Miyamoto, Yoichi; Sasaki, Mitsuho; Miyata, Haruhiko; Monobe, Yoko; Nagai, Masahiro; Otani, Mayumi; Whiley, Penny A. F.; Morohoshi, Akane; Oki, Shinya; Matsuda, Junichiro; Akagi, Ken‐ichi; Adachi, Jun; Okabe, Masaru; Ikawa, Masahito; Yoneda, Yoshihiro; Loveland, Kate L; Oka, Masahiro

doi:10.1096/fj.202000768rr

Cited by 18 publications

(24 citation statements)

References 55 publications

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“…Via individual subtypes that mediate the transport of different sets of cargo, importin αs can function as regulatory switches of gene expression [6], responsible for central cellular functions such as proliferation and differentiation [7][8][9]. Characterization of importin αs at a cellular level has revealed wide roles of importin α both inside and outside of canonical nucleocytoplasmic transport function [10][11][12][13]. However, further characterization is necessary to fully understand the implications of importin αs in physiological contexts.…”

Section: Introductionmentioning

confidence: 99%

Effects of Importin α1/KPNA1 deletion and adolescent social isolation stress on psychiatric disorder-associated behaviors in mice

et al. 2021

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Importin α1/KPNA1 is a member of the Importin α family widely present in the mammalian brain and has been characterized as a regulator of neuronal differentiation, synaptic functionality, and anxiety-like behavior. In humans, a de novo mutation of the KPNA1 (human Importin α5) gene has been linked with schizophrenia; however, the precise roles of KPNA1 in disorder-related behaviors are still unknown. Moreover, as recent studies have highlighted the importance of gene-environment interactions in the development of psychiatric disorders, we investigated the effects of Kpna1 deletion and social isolation stress, a paradigm that models social stress factors found in human patients, on psychiatric disorder-related behaviors in mice. Through assessment in a behavioral battery, we found that Kpna1 knockout resulted in the following behavioral phenotype: (1) decreased anxiety-like behavior in an elevated plus maze test, (2) short term memory deficits in novel object recognition test (3) impaired sensorimotor gating in a prepulse inhibition test. Importantly, exposure to social isolation stress resulted in additional behavioral abnormalities where isolated Kpna1 knockout mice exhibited: (1) impaired aversive learning and/or memory in the inhibitory avoidance test, as well as (2) increased depression-like behavior in the forced swim test. Furthermore, we investigated whether mice showed alterations in plasma levels of stress-associated signal molecules (corticosterone, cytokines, hormones, receptors), and found that Kpna1 knockout significantly altered levels of corticosterone and LIX (CXCL5). Moreover, significant decreases in the level of prolactin were found in all groups except for group-housed wild type mice. Our findings demonstrate that Kpna1 deletion can trigger widespread behavioral abnormalities associated with psychiatric disorders, some of which were further exacerbated by exposure to adolescent social isolation. The use of Kpna1 knockout mice as a model for psychiatric disorders may show promise for further investigation of gene-environment interactions involved in the pathogenesis of psychiatric disorders.

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Section: Introductionmentioning

confidence: 99%

Effects of Importin α1/KPNA1 deletion and adolescent social isolation stress on psychiatric disorder-associated behaviors in mice

et al. 2021

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“…KPNA4 gene, also named Importin Subunit Alpha-4, encodes a protein that plays a central role in the transport of cargo from the cytoplasm to the nucleus. Male knock-out mice for importin α4 were subfertile and yielded smaller litter sizes than wild-type males, indicating that this gene is critical for an appropriate spermatozoa morphology in mice [ 107 ]. BANK1 , RPL17 and RPS15A , which were downregulated under HS, are present in the enriched GO terms related with the regulation of protein, peptides and amide biosynthesis, metabolic processes and translation.…”

Section: Discussionmentioning

confidence: 99%

Exploring the ovine sperm transcriptome by RNAseq techniques. I Effect of seasonal conditions on transcripts abundance

et al. 2022

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Understanding the cell molecular changes occurring as a results of climatic circumstances is crucial in the current days in which climate change and global warming are one of the most serious challenges that living organisms have to face. Sperm are one of the mammals’ cells most sensitive to heat, therefore evaluating the impact of seasonal changes in terms of its transcriptional activity can contribute to elucidate how these cells cope with heat stress events. We sequenced the total sperm RNA from 64 ejaculates, 28 collected in summer and 36 collected in autumn, from 40 Manchega rams. A highly rich transcriptome (11,896 different transcripts) with 90 protein coding genes that exceed an average number of 5000 counts were found. Comparing transcriptome in the summer and autumn ejaculates, 236 significant differential abundance genes were assessed, most of them (228) downregulated. The main functions that these genes are related to sexual reproduction and negative regulation of protein metabolic processes and kinase activity. Sperm response to heat stress supposes a drastic decrease of the transcriptional activity, and the upregulation of only a few genes related with the basic functions to maintain the organisms’ homeostasis and surviving. Rams’ spermatozoids carry remnant mRNAs which are retrospectively indicators of events occurring along the spermatogenesis process, including abiotic factors such as environmental temperature.

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“…Homozygous Kpna3 knockout (KO) and wild type (WT) mice on a C57BL6/NJcl (CLEA Japan Inc., Tokyo, Japan) background were generated at the Institute for Protein Research, Osaka University, by crossing male and female Kpna3 heterozygous mice. The generation of Kpna3 KO mice (12B1 line) and genotyping methods have been previously described ( Miyamoto et al, 2020 ). Mice were housed on a 12-h light/dark cycle (Light: 0800–2000, Dark: 2000–0800) in a quiet environment with room temperature maintained at 24°C ± 2°C.…”

Section: Methodsmentioning

confidence: 99%

Importin α3 (KPNA3) Deficiency Augments Effortful Reward-Seeking Behavior in Mice

et al. 2022

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Importin α3 (Gene: Kpna3, the ortholog of human Importin α4) is a member of the importin α family and participates in nucleocytoplasmic transport by forming trimeric complexes between cargo proteins and importin β1. Evidence from human studies has indicated that single nucleotide polymorphisms (SNP) in the KPNA3 gene are associated with the occurrence of several psychiatric disorders accompanied by abnormal reward-related behavior, including schizophrenia, major depression, and substance addiction. However, the precise roles of importin α3 in controlling reward processing and motivation are still unclear. In this study, we evaluated the behavioral effects of Kpna3 knockout (KO) in mice on performance in touchscreen operant chamber-based tasks evaluating simple (fixed-ratio) and effortful (progressive-ratio) reward-seeking behaviors. While Kpna3 KO mice showed no significant differences in operant reward learning on a fixed-ratio schedule, they demonstrated significantly increased motivation (increased break point) to instrumentally respond for sucrose on a progressive-ratio schedule. We additionally measured the number of c-Fos-positive cells, a marker of neural activity, in 20 regions of the brain and identified a network of brain regions based on their interregional correlation coefficients. Network and graph-theoretic analyses suggested that Kpna3 deficiency enhanced overall interregional functional connectivity. These findings suggest the importance of Kpna3 in motivational control and indicate that Kpna3 KO mice may be an attractive line for modeling motivational abnormalities associated with several psychiatric disorders.

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Genetic loss of importin α4 causes abnormal sperm morphology and impacts on male fertility in mouse

Cited by 18 publications

References 55 publications

Effects of Importin α1/KPNA1 deletion and adolescent social isolation stress on psychiatric disorder-associated behaviors in mice

Effects of Importin α1/KPNA1 deletion and adolescent social isolation stress on psychiatric disorder-associated behaviors in mice

Exploring the ovine sperm transcriptome by RNAseq techniques. I Effect of seasonal conditions on transcripts abundance

Importin α3 (KPNA3) Deficiency Augments Effortful Reward-Seeking Behavior in Mice

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