Biology subjects

Kimura, S.

Publications and source records attributed to Kimura, S..

At least 19 recordsLinked to original sources

bioRxiv2026

Associations between striatal neurochemical changes and resting-state functional connectivity following transcranial temporal interference stimulation

Background Non-invasive modulation of deep brain structures remains a major challenge in human neuroscience and neurorehabilitation. Transcranial temporal interference stimulation (tTIS) has emerged as a promising approach for engaging subcortical regions, but its effects on striatal neurochemical markers and functional connectivity remain unclear. Objective To investigate whether 20-Hz tTIS designed to target the right striatum modulates GABA+ and glutamate-glutamine complex (Glx) levels and whether neurochemical changes are associated with changes in resting-state functional connectivity. Methods Thirty-four healthy right-handed participants were randomly assigned to the tTIS group (20-Hz beat frequency) or sham group (0-Hz frequency difference). Participants underwent proton magnetic resonance spectroscopy (1H-MRS) and resting-state fMRI before and after 30 min of stimulation. One participant in the tTIS group was excluded from the 1H-MRS analyses because of data corruption. Results The direct between-group difference in Glx change did not reach statistical significance, although the tTIS group showed a numerically greater reduction than the sham group (p = 0.066). Exploratory within-group analyses showed a significant decrease in striatal Glx in the tTIS group (p < 0.001), whereas the decrease in the sham group was not significant. No significant GABA+ changes were observed within or between groups. The association between striatal Glx change and functional connectivity change differed between groups in the sensorimotor cortex, right parahippocampal gyrus, and bilateral fusiform gyri. Conclusion These exploratory findings suggest that 20-Hz tTIS may be associated with striatal Glx modulation and group-dependent coupling between neurochemical and cortico-subcortical network changes.

neuroscience↗

bioRxiv2026

Loss of NKX2-1 predisposes thyroid to neoplasm development through regulation of oxidative stress

Many factors including ionizing radiation and iodine deficiency are known to increase thyroid carcinogenesis risk. Our dataset analysis of The Cancer Genome Atlas (TCGA) showed that lower mRNA expression of NK2 homeobox 1 (NKX2-1) transcription factor, a master regulator of genesis, homeostasis, and function of thyroid, is linked to poor prognosis of papillary thyroid cancer patients. Here we provide the findings that thyroid-specific Nkx2-1 conditional knockout (Nkx2-1{Delta}T) mice develop thyroid adenoma and carcinoma in higher frequency with combined exposure to radiation and iodine deficiency than control Nkx2-1fl/fl mice. Iodine deficiency caused oxidative stress, which subsequently resulted in DNA damage, leading to transformation of thyroid follicular cells. RNA-seq gene set enrichment analysis indicated higher production of reactive oxygen species (ROS) in the thyroids of Nkx2-1{Delta}T as compared to Nkx2-1fl/fl mice with combined exposure to radiation and iodine deficiency. This was accompanied by a feedback induction of SOD3 (superoxide dismutase 3) and GPX2 (glutathione peroxidase 2). These antioxidants were naturally expressed at higher levels in the thyroids of Nkx2-1{Delta}T than Nkx2-1fl/fl mice without iodine deficiency or radiation. Nkx2-1{Delta}T thyroids exhibited abnormal follicle architecture and up-regulation of Acox2 (encoding acyl-CoA oxidase 2), which produces hydrogen peroxide. These results suggest that loss of NKX2-1 may contribute to excess ROS production, which elevates basal oxidative stress resulting in the promotion of ROS-induced carcinogenesis. We propose a role for NKX2-1 as a regulator of ROS production homeostasis in the thyroid. Its disturbance would dispose thyroid follicular cells more vulnerable to the ROS-producing carcinogens.

cancer biology↗

bioRxiv2026

Phylogenomics, Biogeography, and a New Family-level Classification of Silversides, Rainbowfishes, and Allies (Teleostei: Atheriniformes)

The order Atheriniformes (silversides, rainbowfishes, and blue-eyes) is a globally distributed group of fishes with frequent evolutionary transitions between marine and freshwater ecosystems. However, understanding the tempo and mode of these transitions has been hampered by poor phylogenetic resolution and limited taxonomic sampling, particularly within the suborder Atherinoidei. We generated a phylogenomic dataset of 1,100 exon loci for 150 species to resolve interfamilial relationships and reconstruct the groups biogeographic history. We were also able to incorporate a large number of existing GenBank sequences, producing a phylogeny with 265 species sampled for at least some genetic data (67% of known species diversity). While the New World suborder Atherinopsidae is well-resolved, we found that the family Atherinidae is polyphyletic across all analyses. We propose a revised classification that restricts Atherinidae to the genus Atherina and recognizes Atherinomoridae and Craterocephalidae as separate families. Our biogeographic inferences using explicit geographic areas suggests more frequent marine-to-freshwater transitions than previously inferred with simplified binary (marine vs. freshwater) coding, and uncover habitat transitions where marine ancestors may have gone extinct. These results highlight how explicit geographic modeling can uncover marine ancestry erased by extinction, providing a robust phylogenetic framework for future evolutionary studies of Atheriniformes.

evolutionary biology↗

bioRxiv2026

The circadian clock gates lateral root development

Lateral root (LR) formation remodels root architecture, yet how temporal information integrates with hormonal cues remains unclear. We show that the circadian clock component EARLY FLOWERING 3 (ELF3) acts as a temporal gatekeeper of root organogenesis in Arabidopsis thaliana. Time-resolved transcriptomics, imaging, and genetics reveal that ELF3 restrains hormone-induced pericycle proliferation by maintaining rhythmic expression of key regulators under callus-inducing conditions. Loss of ELF3 disrupts rhythmic gene expression, enhancing callus growth and accelerating LR development. ELF3 functions through its target LNK1 to regulate the MADS-box genes AGL14 and AGL20. Notably, callus-inducing signals partially restore rhythmicity in elf3 mutants, revealing feedback from hormonal signaling to the circadian system. These findings identify ELF3 as an integrator of circadian and hormonal inputs that temporally constrains root developmental plasticity.

plant biology↗

bioRxiv2025

Environmental exosomes: Evidence of extracellular RNA release by aquatic organisms

Aquatic organisms continuously interact with surrounding water, yet whether they release extracellular vesicles remains unknown. We hypothesized that pearl oysters (Pinctada fucata) release exosomes/small extracellular vesicles (sEVs) into the aquatic environment. To this end, we collected exosomes/sEV-sized components by ultrafiltration from tank water and open-sea culture areas. Microscopy revealed abundant vesicles consistent with exosome/sEV size, and RNA sequencing identified oyster-specific piRNAs that matched sequences previously detected in hemolymph exosomes. These findings demonstrated that pearl oysters actively released exosomes containing species-specific nucleic acids into surrounding water. We propose referring to these vesicles as environmental exosomes/environmental sEVs (eExosomes/esEVs). This finding suggests that aquatic exosomes serve as carriers of RNA and may contribute to inter-organismal communication networks. Beyond their functional role, eExosomes/esEVs also hold promise as novel targets for environmental DNA/RNA (eDNA/eRNA) analysis, offering new opportunities for ecological monitoring and biodiversity research.

ecology↗

bioRxiv2025

Dietary soy shapes murine microbiota to consolidate the mucosal IgA response through T follicular helper cells

The commensal microbiota plays a crucial role in shaping mucosal immunity, particularly in the induction of T follicular helper (Tfh) cells and IgA production. Here, we demonstrate that dietary soy elicits a robust Tfh cell and IgA response in Peyers patches of weaning mice. Soy feeding promotes the expansion of two principal commensal bacterial species, Limosilactobacillus reuteri and Muribaculum intestinale. Mechanistically, L. reuteri provides cognate antigens for Tfh cell activation, while M. intestinale functions as an adjuvant by promoting IL-1{beta} production from myeloid cells. The resulting IgA exhibits polyreactivity and enhances protection against Salmonella infection. These findings highlight the specific interplay among dietary components, intestinal microbiota, and mucosal immunity, thereby establishing a diet-microbe-immune axis that shapes host defense in early life. This axis represents a promising therapeutic target for developing novel strategies to enhance resistance to enteric pathogens. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=170 HEIGHT=200 SRC="FIGDIR/small/669459v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@1ae8277org.highwire.dtl.DTLVardef@1f787ceorg.highwire.dtl.DTLVardef@1f51fd6org.highwire.dtl.DTLVardef@1fd3439_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIDietary soy promotes T follicular helper (Tfh) cell and IgA responses in the Peyers patches of weaning mice. C_LIO_LISoy enhances the colonization of two key commensals, Limosilactobacillus reuteri and Muribaculum intestinale, in the small intestine. C_LIO_LIThese two bacteria synergize to drive mucosal immunity: L. reuteri provides cognate antigens, while M. intestinale provides an adjuvant signal by promoting IL-1{beta} production from myeloid cells. C_LIO_LISoy-induced IgA is polyreactive and protects against Salmonella infection. C_LI

immunology↗

bioRxiv2025

Remodeling of tRNA modification in Trypanosoma cruzi life forms

Trypanosoma cruzi, the etiological agent of Chagas disease, infects millions of people in the Americas. This parasite undergoes drastic changes in its morphology and metabolism between infective and noninfective forms through global remodeling of its proteome. Chemical modification of tRNA (tRNA modification) contributes to the control of protein expression by modulating the codon decoding process. However, knowledge of tRNA modification profiles, the enzymes that create modifications and their regulation in different cellular conditions is largely restricted to relatively few model organisms. Here, we profile tRNA modifications in both infective and noninfective forms of T. cruzi to probe their dynamic changes. Genome mining of tRNA modifying enzymes identified 66 putative tRNA modifying enzymes in T. cruzi, each responsible for at least one of fifty-seven modifications. tRNA sequencing detected reverse transcription-derived signatures at 182 sites in T. cruzi tRNAs that are likely derived from 18 tRNA modifications. tRNA modifications and tRNA modification enzymes are differentially modulated across the life stages of T. cruzi. We found that hydroxywybutosine (OHyW) at position 37 on tRNAPhe had a reduced level in the infective form (metacyclic trypomastigote) and the associated modification enzyme Tyw1a exhibited reduced expression in this stage. Knockout of Tyw1a increased the differentiation from epimastigote (noninfective form) to metacyclic trypomastigote, suggesting that OHyW37 modification levels control the rate of metacyclogenesis. Overall, our findings suggest that the global regulation of tRNA modifications in the life stages of T. cruzi plays a critical role in the differentiation of this parasite.

molecular biology↗

bioRxiv2025

Estimating fruit tree growth curves in breeding field using fragmented longitudinal data: An application to citrus hybrid seedlings

Vegetative and reproductive growth in fruit trees is interconnected, and analyzing this relationship can provide valuable insights into fruit quality. However, characterizing vegetative growth through growth models is challenging because of the difficulty in obtaining longitudinal data, given the slow growth rate. In breeding fields, in contrast, seedlings of different ages are planted, allowing for simultaneous measurements that yield a dataset resembling longitudinal data with missing values --termed "fragmented longitudinal data." Because longitudinal data are obtained from a single measurement, they can potentially shorten the period required for growth curve estimation. Bayesian nonlinear models offer advantages in estimating curves from incomplete data. In this study, we generated fragmented longitudinal data using genome data with 45,929 markers from 624 citrus hybrid seedlings and applied a Bayesian nonlinear model to explore its potential. We also incorporated genomic information into the model to assess the impact of the estimation accuracy. Our simulations indicated that the Bayesian nonlinear models ability to interpolate missing values significantly improved the estimation performance. At best, the mean square error of the parameter characterizing the later growth stage was reduced by 84.3 mm2. Although the improvement from incorporating genomic information was modest, it still surpassed models that lacked genomic data. We also predicted the curves of untested individuals using the estimated parameters. Although the prediction accuracy of each parameter measured by the correlation coefficient was lower than 0.5, one parameter consistently showed a better accuracy. Further research is required to reveal the advantages of integrating genomic data for better predictions.

genetics↗

bioRxiv2024

The heterogeneity of dermal mesenchymal cells reproduced in skin equivalents regulate barrier function and elasticity.

The heterogeneity of dermal mesenchymal cells, including perivascular mesenchymal cells and papillary and reticular fibroblasts, plays critical roles in skin homeostasis. Herein, we present human skin equivalents (HSEs), in which pericytes, papillary fibroblasts, and reticular fibroblasts are spatially organized through autonomous three-cell interactions among epidermal keratinocytes, dermal fibroblasts, and vascular endothelial cells. The replication of dermal mesenchymal cell heterogeneity enhances skin functions, including epithelialization, epidermal barrier formation, and dermal elasticity, enabling in vitro evaluation of drug efficacy using methodologies that are identical to those used in human clinical studies. Furthermore, ascorbic acid-induced epidermal turnover and synthesis of well-aligned extracellular matrix via perivascular niche cells play crucial roles in improving skin barrier function and elasticity. Therefore, HSEs with heterogeneous dermal mesenchymal cells may improve our understanding of the mechanisms underlying skin homeostasis through cell-to-cell communication and serve as a model to animal experiments for developing precision medicine.

bioengineering↗

bioRxiv2024

Identification of M-Sec as a unique cellular regulator of CSF-1 receptor activation

Fms, the CSF-1 receptor encoding tyrosine kinase, is essential for tissue macrophage development, and the therapeutic target for many tumors. However, it is not completely understood how Fms activation is regulated. Here, we identify the cellular protein M-Sec as a unique regulator of Fms. In macrophages, Fms forms large aggregates via unknown mechanisms. We found that the inhibition or knockdown of reduced Fms aggregate formation and functional response of macrophages to CSF-1, which was consistent with reduced Fms activation after CSF-1 stimulation. When expressed in 293 cells, M-Sec augmented Fms aggregate formation and CSF-1-induced Fms activation. CSF-1 and M-Sec bind the cellular phosphatidylinositol 4,5-biphosphate (PIP2). The removal of PIP2-binding motif of Fms or M-Sec, or the depletion of cellular PIP2 reduced Fms aggregate formation. Moreover, M-Sec altered cellular distribution of PIP2. Since CSF-1-induced dimerization of Fms is critical for its activation, our findings suggest that M-Sec augments large Fms aggregate formation via PIP2, which brings Fms monomers close to each other and enables the efficient dimerization and activation of Fms in response to CSF-1.

molecular biology↗

bioRxiv2024

Formation of giant ER sheets by pentadecanoic acid causes lipotoxicity in fission yeast

Excess amounts of saturated fatty acids are toxic to organisms, a condition termed lipotoxicity, which is often accompanied by pleiotropic cellular and tissue dysfunction. Here we show that pentadecanoic acid (C15:0) exerts toxicity on the fission yeast Schizosaccharomyces pombe by generating an aberrantly planar endoplasmic reticulum (ER) structure, which we named a "giant ER sheet." Untargeted lipidomics revealed that C15:0 is incorporated into complex lipids depending on an acyl-CoA ligase Lcf1 and an acyl-CoA transferase Slc1, thereby increasing the saturation level of the acyl chains. The toxicity and giant ER sheet formation were abolished by deleting Lcf1 or Slc1, indicating that the incorporation of C15:0 into glycerophospholipids causes giant ER sheet formation. The giant ER sheets disrupted the correct migration of Mid1, a protein determining the cell division site, and physically blocked septum formation, hindering correct cell separation. Our results suggest that the ER is the primary site targeted by saturated fatty acids, leading to lipotoxicity.

cell biology↗

bioRxiv2024

Chemical genetics reveals cross-activation of plant developmental signaling by the immune peptide-receptor pathway

Cells sense and integrate multiple signals to coordinate development and defence. A receptor-kinase signaling pathway for plant stomatal development shares components with the immunity pathway. The mechanism ensuring their signal specificities remains unclear. Using chemical genetics, here we report the identification of a small molecule, kC9, that triggers excessive stomatal differentiation by inhibiting the canonical ERECTA receptor-kinase pathway. kC9 binds to and inhibits the downstream MAP kinase MPK6, perturbing its substrate interaction. Strikingly, activation of immune signaling by a bacterial flagellin peptide nullified kC9s effects on stomatal development. This cross-activation of stomatal development by immune signaling depends on the immune receptor FLS2 and occurs even in the absence of kC9 if the ERECTA-family receptor population becomes suboptimal. Furthermore, proliferating stomatal-lineage cells are vulnerable to the immune signal penetration. Our findings suggest that the signal specificity between development and immunity can be ensured by MAP Kinase homeostasis reflecting the availability of upstream receptors, thereby providing a novel view on signal specificity.

plant biology↗

bioRxiv2024

Integrating tDNA Epigenomics and Expression with Codon Usage Unravel an Intricate Connection with Protein Expression Dynamics in Trypanosoma cruzi

Codon usage bias impacts protein expression across all kingdoms of life, including trypanosomatids. These protozoa, such as the Trypanosoma cruzi, primarily regulate their protein-coding genes through posttranscriptional mechanisms. Here, we integrated analyses of codon usage with multiple high-throughput sequencing data to investigate whether codon usage bias is present into surface virulence factors (disruptive compartment), conserved housekeeping proteins (core compartment), and proteins involved in the developmental stages of T. cruzi. For the first time in trypanosomatids, tRNA sequencing was employed to reveal coadaptation between codon usage and anticodon availability. Despite notable differences in the proteomes of infective and non-infective forms, they exhibited similar pools of tRNAs and similar codon usage preferences. We observed that open chromatin levels of tRNA genes correlate with tRNA expression in non-infective forms, but not in infective forms, suggesting chromatin states do not control the tRNA pool in the latter. Our analysis also revealed a relationship between anticodon:codon pairing modes and protein abundance. Highly expressed mRNAs favored Watson- Crick base pairing, whereas less expressed mRNAs displayed more wobble base pairing. Overall, our findings suggest that protein expression in T. cruzi is influenced by a combination of codon usage bias, tRNA abundance, and anticodon:codon pairing modes. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC="FIGDIR/small/602108v2_ufig1.gif" ALT="Figure 1"> View larger version (16K): org.highwire.dtl.DTLVardef@1f63f77org.highwire.dtl.DTLVardef@1c0abf8org.highwire.dtl.DTLVardef@5a4988org.highwire.dtl.DTLVardef@1918f49_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2024

Transcriptomic analysis of the juvenile to adult transition in the mouse corpus callosum

The corpus callosum, a major white matter tract in the brain, undergoes age-related functional changes. To extend our investigation of age-related gene expression dynamics in the mouse corpus callosum, we compared RNA-seq data from 2-week-old and 12-week-old wild-type C57BL/6J mice and identified the differentially expressed genes (e.g., Serpinb1a, Ndrg1, Dnmt3a, etc.) between these ages. Interestingly, we found that genes highly expressed in myelinating oligodendrocytes were upregulated in 12-week-old mice compared to 2-week-old mice, while genes highly expressed in oligodendrocyte precursor cells (OPCs) and newly formed oligodendrocytes were downregulated. Furthermore, by comparing these genes with the datasets from 20-week-old and 96-week-old mice, we identified novel sets of genes with age-dependent variations in the corpus callosum. These gene expression changes potentially affect key biological pathways and may be closely linked to age-related neurological disorders, including dementia and stroke. Therefore, our results provide an additional dataset to explore age-dependent gene expression dynamics of oligodendrocyte lineage cells in the corpus callosum.

neuroscience↗

bioRxiv2024

Systematic mutagenesis assay promotes comprehension of the strand-bias laws for mutations induced by oxidative DNA damage

We have recently developed an efficient and sensitive method for analyzing mutations caused by various environmental and endogenous factors which utilizes nucleotide-barcoded supF shuttle vector libraries with a multiplexed NGS assay, referred to hereafter as supF NGS assay. Ionizing-radiation-induced cancer is known to be difficult to distinguish from spontaneous cancer, especially in the case of low-dose and low-dose-rate exposure, and discerning the underlying mechanisms of ionizing-radiation-induced cancer, especially the relationship between mutagenesis and carcinogenesis, is likely to be an arduous task. In the present study, we have attempted to address the mutations characteristic for exposure to low levels of ionizing radiation by using the supF NGS assay. As a result, a significant increase in mutations was detected at cytosines and guanines within 5-TC-3:5-GA-3 sites following chronic gamma-irradiation at a dose-rate of 1 Gy per day for the duration of 2 days. Since the number of detected mutations exceeded the expectations based on the quantity of DNA-damage induced by irradiation, we proceeded to explore the possibilities that a single DNA-lesion induced by irradiation may cause amplification of mutations. For this purpose, we utilized shuttle vector libraries with a single 8-oxo-7,8-dihydroguanine (8-oxo-G)-damaged residue introduced at different sites via an in vitro enzymatic method. Through a set of experiments, we revealed that a single 8-oxo-G-damaged residue can become a trigger for peripheral mutagenesis; intense generation of strand-biased mutations occured at 5-TC-3:5-GA-3 sites with specific localization in the secondary structures of single-stranded DNA, more frequently than not at sites different from the 8-oxo-G-damaged sites. Thus, this study provides a novel prospect for the role of DNA-lesions induced by environmentally or endogenously generated ROS in additional mutations. The high-performance mutagenesis assay presented in this study will advance research aimed at uncovering the mechanisms of mutagenesis and the intricacies relevant to carcinogenesis.

cell biology↗

bioRxiv2024

CAP peptide artificially induces insect gall

Galls caused by gall-inducing insects in their host plants clearly illustrate the concept of extended phenotype, which refers to traits expressed in a host organism when manipulated by a parasite. Candidate effector molecules involved in gall formation, such as phytohormones, amino acids, and proteins, have been reported in numerous studies. However, to date, no attempts to artificially regenerate gall structures using effector candidates have been reported. In this study, we tested the peptide from Cysteine-rich secretory proteins, Antigen 5, and Pathogenesis-related 1 proteins, CAP peptide as a gall-inducing effector candidate obtained from transcripts isolated from the horned gall aphid, (Schlechtendalia chinensis) through in silico screening and the Arabidopsis-based gall-forming assay, which is a bioassay system for analysing the molecular mechanisms of gall formation. Furthermore, we succeeded in generating an artificial gall in the host plant Veronica peregrina, without any insect parasitism, using three minimal effector elements: CAP peptide, auxin, and cytokinin. Given the strong similarities observed in organ structure with a central cavity and three types of tissue and gene expression patterns between the native and artificial galls, we concluded that CAP peptide is a general gall-inducing effector peptide secreted by gall-inducing insects.

molecular biology↗

bioRxiv2023

Transcriptomic Landscape of Hyperthyroidism in Mice Overexpressing Thyroid Stimulating Hormone

Hyperthyroidism is a condition with excessive thyroid hormone secretion. Activation of thyroid stimulating hormone receptor (TSHR) fundamentally leads to hyperthyroidism. The details of TSHR signaling remain to be elucidated. We conducted transcriptome analyses for hyperthyroid mice that we generated by overexpressing TSH. TSH overexpression via hydrodynamic gene delivery with pLIVE-TSHB and pLIVE-CGA vectors consistently caused hyperthyroidism and goiters for at least 4 weeks in C57BL/6J mice. RNA sequencing analysis of their thyroid glands revealed that thiamazole slightly changed the thyroid transcriptome, which reinforces a conventional theory that thiamazole decreases thyroid hormone secretion via inhibition of thyroid peroxidase activity. Meanwhile, TSH overexpression drastically changed the thyroid transcriptome. In particular, enrichment analyses identified the cell cycle, phosphatidylinositol-3 kinase/Akt pathway, and Ras-related protein 1 pathway as possibly associated with goiter development. Regarding the role of TSHR signaling in hyperthyroidism, it is noteworthy that Slc26a4 was exclusively upregulated among genes crucial to thyroid hormone secretion at both 1 and 4 weeks after hydrodynamic gene delivery. To verify the relationship between this upregulation and hyperthyroidism, we overexpressed TSH in Slc26a4 knockout mice. TSH overexpression caused hyperthyroidism in Slc26a4 knockout mice, equivalent to that in control mice. To summarize, we analyzed hyperthyroid mice generated by TSH overexpression. We did not observe significant changes in known genes and pathways involved in thyroid hormone secretion. Thus, our datasets might include candidate genes that have not yet been identified as regulators of thyroid function. Our transcriptome datasets regarding hyperthyroidism can contribute to future research on TSHR signaling.

physiology↗

bioRxiv2023

Akr1b7 functions as a master regulator in ovarian aging

At the beginning of ovarian aging, the ovulation of immature oocytes is accelerated, leading to the arrest of ovulation despite the remaining oocytes. Here, RNA expression in the ovarian aging of mice is comprehensively analyzed during the estrous cycle after ovulation stimulation. The aldo-keto reductase Akr1b7 pathway transiently activated in the ovaries of young mice disappears in those of old mice. Akr1b7--/-- mice attenuate oocyte Akt activation essential for the follicular development in primordial follicles, and enhanced ovulation in immature oocytes. The estrous cycle is extended because of the prolonged diestrous stage by a sustained progesterone level in Akr1b7--/--mice ovaries, which is caused by the decline of Cyp17a1, a major metabolic enzyme of progesterone in Akr1b7-expressed theca cell layers. In summary, the decreased Akr1b7 pathway causes ovulation of immature oocytes and a prolonged estrous cycle, typical symptoms of ovarian aging.

molecular biology↗