遗传Pub Date : 2026-03-01DOI: 10.16288/j.yczz.25-190
Ya-Xin Deng, Bao-Jun Ding, Hong-Chun Li, Song Chen, Ying Zhang, Bo Zhou, Zhen Zhang
{"title":"Multi-stage transcriptomic analysis of mouse embryonic lethality induced by homozygous knockout of the <i>Vrtn</i> gene.","authors":"Ya-Xin Deng, Bao-Jun Ding, Hong-Chun Li, Song Chen, Ying Zhang, Bo Zhou, Zhen Zhang","doi":"10.16288/j.yczz.25-190","DOIUrl":"10.16288/j.yczz.25-190","url":null,"abstract":"<p><p>The <i>Vrtn</i> gene, a recently identified regulator of embryonic development and stem cell pluripotency, is essential for embryonic survival, as its homozygous knockout (<i>Vrtn</i><sup>-/-</sup>) leads to lethality in mice at approximately embryonic day 12.5 (E12.5). To elucidate the underlying lethal mechanism, an integrated approach combining morphological observation, multi-stage transcriptomic analysis, and functional validation experiments was employed to systematically investigate the developmental disorders caused by <i>Vrtn</i> deficiency. Morphological observation showed that <i>Vrtn</i><sup>-</sup>/<sup>-</sup> embryos exhibited significant abnormalities at developmental stages E9.0, E9.5, E10.0, E10.5, and E11.0, including shortened body axis, defective neural tube closure, aberrant somite differentiation, and cardiovascular malformations, accompanied by overall developmental delay. At the molecular level, through RNA sequencing and qRT-PCR validation revealed that <i>Vrtn</i> deficiency not only suppressed the expression of genes critical for somitogenesis (<i>Hoxa2</i>, <i>Hes5</i>), neurodevelopment (<i>Nefm</i>, <i>Nefl</i>), and the hematopoietic system (<i>Hbb-bh1</i>, <i>Klf1</i>), but also aberrantly activated genes associated with apoptosis (<i>Crabp2</i>, <i>Fam162a</i>) and lipid metabolism (<i>Apom</i>, <i>Apoe</i>). TUNEL staining showed that the level of apoptosis was significantly increased in <i>Vrtn</i><sup>-/-</sup> embryos. Meanwhile, immunofluorescence detection of Hif-1α indicated that the hypoxic stress response was aberrantly activated. Furthermore, the widespread dysregulation of genes involved in thyroid hormone transport (<i>Ttr</i>), DNA damage stress (<i>Ddit4</i>), and lipid metabolism (<i>Apoa4</i>, <i>Apoa1</i>) collectively exacerbated the developmental imbalance, ultimately leading to embryonic death. A cross-species analysis demonstrated that <i>VRTN</i> knockdown in human embryonic stem cells (hESCs) significantly suppressed the expression of core angiogenic genes (<i>VEGFA</i>, <i>COL1A1</i> and <i>HES1</i>), a finding consistent with public database analyses indicating a strong association between <i>VRTN</i> and the hypoxic response. In conclusion, this study elucidates that <i>Vrtn</i> functions as a regulatory gene that maintains embryonic homeostasis by orchestrating multiple key developmental processes, including somitogenesis, neural differentiation, angiogenesis, and the hypoxic stress response. This discovery not only deepens the understanding of the role of <i>Vrtn</i> in embryonic development but also provides a new perspective for deciphering the pathogenesis of related hereditary diseases.</p>","PeriodicalId":35536,"journal":{"name":"遗传","volume":"48 3","pages":"313-330"},"PeriodicalIF":0.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147475661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Genomic prediction of growth trait phenotypes in Large White pigs using a chromosome-encoded multi-head self-attention model.","authors":"Wen-Xuan Zhou, Zhen-Jian Zhao, Dong Chen, Sheng-di Cui, Jun-Ge Wang, Zi-Yang Chen, Shi-Xin Yu, Jia-Miao Chen, Yao-Xi Zhou, Run-Jie Huang, Guo-Qing Tang","doi":"10.16288/j.yczz.25-228","DOIUrl":"10.16288/j.yczz.25-228","url":null,"abstract":"<p><p>With the widespread adoption of genome sequencing technologies, predicting complex traits using genomic markers has become a key component in breeding programs. However, the high dimensionality and sparsity of genomic data, along with the complex nonlinear interactions among genetic markers, significantly increase the difficulty of accurate data analysis and the cost of hardware deployment. Therefore, this study proposes a chromosome-encoded multi-head self-attention model, named ChrFormer, for genomic prediction. The model employs a chromosome encoder to compress whole-genome SNP data into 20 chromosome-specific feature vectors and one global feature vector. It leverages the multi-head self-attention mechanism to dynamically capture long-range interactive effects across chromosomes, and a multilayer perceptron (MLP) precisely predicts phenotype from the refined genomic features. The study selected genotyping data from 50,000 SNPs of 4,875 Large White pigs, along with four key production traits, including backfat thickness at 100 kg and 115 kg, and age at 100 kg and 115 kg. A ten-fold cross-validation approach and the Pearson correlation coefficient were used to evaluate prediction accuracy. The predictive performance of ChrFormer was systematically compared with genomic best linear unbiased prediction (GBLUP), Bayesian method A (BayesA), and representative deep learning methods, including the visual geometry group (VGG) network and the feedforward neural network (FNN). Furthermore, the study analyzed the strengths and weaknesses of each deep learning model from multiple aspects, including the number of model parameters, training time, and the extent of overfitting. The results show that ChrFormer significantly outperforms the VGG and FNN deep learning models in predictive accuracy across all tested traits. For three of the traits (backfat thickness at 100 kg and 115 kg, and days to 115 kg), its prediction accuracy surpasses that of the traditional GBLUP and BayesA methods. Although ChrFormer requires a longer training time per iteration (54.88 s), its number of parameters is only about one-tenth of that of VGG and FNN, and it demonstrates more stable resistance to overfitting. These results demonstrate that the self-attention-based ChrFormer is a practical tool for genomic phenotype prediction in animal breeding, and its lightweight architecture and stable performance offer a readily deployable solution for breeding stations with limited computational resources.</p>","PeriodicalId":35536,"journal":{"name":"遗传","volume":"48 3","pages":"331-340"},"PeriodicalIF":0.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147475671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
遗传Pub Date : 2026-02-20DOI: 10.16288/j.yczz.25-205
Shan Jiang, Yu-Hang Lei, Tian-Ci Liao, Yi Zhong, Mai-Lin Gan, Li Zhu, Lin-Yuan Shen
{"title":"Multidimensional evidence assessment and mechanistic integration of the health effects of red and white meat.","authors":"Shan Jiang, Yu-Hang Lei, Tian-Ci Liao, Yi Zhong, Mai-Lin Gan, Li Zhu, Lin-Yuan Shen","doi":"10.16288/j.yczz.25-205","DOIUrl":"10.16288/j.yczz.25-205","url":null,"abstract":"<p><p>The health effects of red and white meat have been debated for decades, and the conventional species-based binary classification fails to capture their nutritional heterogeneity and differential disease risks. This review reconstructs the meat-health evaluation paradigm by integrating multidisciplinary evidence from epidemiology, molecular biology, and food science. Current findings demonstrate that traditional definitions overlook intra-species variation and inter-species paradoxes, underscoring the need to classify meat more precisely by anatomical cut and processing method. Processed meat, recognized as a Group 1 carcinogen, presents fundamentally distinct hazards from unprocessed red meat; moderate consumption of the latter may allow a reasonable balance between essential nutrients such as heme iron and vitamin B<sub>12</sub> and associated pathophysiological risks. Mechanistically, the adverse effects of red meat are driven by a convergent network involving heme iron, N-glycolylneuraminic acid (Neu5Gc), trimethylamine-N-oxide (TMAO), and processing-derived toxicants including N-nitroso compounds (NOCs), heterocyclic amines (HCAs), and polycyclic aromatic hydrocarbons (PAHs). In contrast, white meat generally lacks these key toxic components and is enriched in omega-3 polyunsaturated fatty acids (PUFAs) such as EPA and DHA, which provide cardioprotective and neuroprotective benefits, although excessive high-temperature cooking may diminish these advantages. Correspondingly, international dietary guidelines are converging toward the principle of \"strictly restrict processed meat, limit unprocessed red meat, and prioritize white meat\". Emerging precision strategies include genetic risk stratification, probiotic and dietary fiber interventions targeting the gut microbiota-TMAO axis, and low-temperature/clean-label processing technologies. Future directions should leverage single-cell and spatial multi-omics to elucidate organ-specific toxicity, build tripartite gene-microbiota-nutrient interaction models to enable individualized risk prediction, and apply CRISPR-based breeding to improve the nutritional-toxicological profile of red meat, while integrating AI-driven personalized dietary guidance. Collectively, these advancements will drive meat consumption toward a more nutritionally optimized, health-protective, and environmentally sustainable paradigm.</p>","PeriodicalId":35536,"journal":{"name":"遗传","volume":"48 2","pages":"177-200"},"PeriodicalIF":0.0,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146158357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
遗传Pub Date : 2026-02-20DOI: 10.16288/j.yczz.25-121
Zi-Tao Peng, Jiong-Chen Lin, Hai-Bo Xie
{"title":"Progress on posttranslational modifications of ciliary tubulin and association with ciliopathies.","authors":"Zi-Tao Peng, Jiong-Chen Lin, Hai-Bo Xie","doi":"10.16288/j.yczz.25-121","DOIUrl":"10.16288/j.yczz.25-121","url":null,"abstract":"<p><p>Cilia are hair-like structures protruding from the surface of eukaryotic cells, composed of a microtubule-based cytoskeleton and bounded by ciliary membrane, which play a crucial role in organ development and homeostasis maintenance in organisms. The ciliary tubulin undergoes several highly conserved posttranslational modifications (PTMs) including acetylation, glutamylation, glycylation and detyrosination. The studies indicate that ciliary tubulin PTMs are adequate to precisely regulate the fine tuning of assembly/disassembly, maintenance, motility, and signaling of cilia. Dysregulated ciliary tubulin PTMs leads to ciliary dysfunction, strongly implicated in human disorders including ciliopathies. Here, we review the current understanding how ciliary tubulin PTMs regulate cilia formation and function, with a focus on their association with human disorders, which may provide novel avenues for therapeutic intervention in ciliopathies.</p>","PeriodicalId":35536,"journal":{"name":"遗传","volume":"48 2","pages":"142-157"},"PeriodicalIF":0.0,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146158372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Research progress on insect codon usage bias.","authors":"Shi-Tian He, Xin-Yi Zhu, Si-Huan Li, Shao-Min Tao, Cheng Pan, Chuan-Lin Yin","doi":"10.16288/j.yczz.25-214","DOIUrl":"10.16288/j.yczz.25-214","url":null,"abstract":"<p><p>Codon usage bias (CUB) refers to the non-random usage of synonymous codons during protein translation. It holds significant value for understanding species evolution, environmental adaptation, gene expression regulation, and population genetic diversity. In this review, we summarize the biological significance of codon usage bias, outline commonly used statistical approaches for its analysis, and provide a comprehensive overview of recent advances in codon usage research within the field of entomology. This work aims to offer new perspective and methodologies insights to support further in-depth studies of codon usage patterns in insects.</p>","PeriodicalId":35536,"journal":{"name":"遗传","volume":"48 2","pages":"158-176"},"PeriodicalIF":0.0,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146158558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
遗传Pub Date : 2026-02-20DOI: 10.16288/j.yczz.25-130
Cui-Cui Jiang, Ke Wu
{"title":"Analysis of <i>STAG1</i> gene variants identified in a patient with intellectual disability and speech delay.","authors":"Cui-Cui Jiang, Ke Wu","doi":"10.16288/j.yczz.25-130","DOIUrl":"10.16288/j.yczz.25-130","url":null,"abstract":"<p><p>Autosomal dominant intellectual developmental disorder (type 47) (OMIM #617635) is associated with heterozygous variants in the <i>STAG1</i> gene (OMIM*604358). The main clinical manifestations include intellectual disability, delayed language development, abnormal facial features, epilepsy, etc. In this study, we performed the whole-exome sequencing (WES) on a 3-year-old child diagnosed with psychomotor developmental delay, and verified candidate gene variants by Sanger sequencing. We constructed a mutant plasmid expression vector and subsequently transfected it into HEK293T cells to preliminarily investigate the pathogenic mechanism of the identified variant. Additionally, we conducted a comprehensive review of previously published literature to systematically summarize the associated clinical phenotypes. WES revealed that the patient harbored the c.500dup (p.Gly168TrpfsTer13) of the <i>STAG1</i> gene, and it was a <i>de novo</i> variant. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as a pathogenic variant (PVS1+PM2_Supporting+PS2_Supporting). <i>In vitro</i> cellular function studies have demonstrated that this variant resulted in a substantial decrease in the expression of mutant mRNA, thereby impairing the production of functional STAG1 protein. Clinical phenotypes associated with <i>STAG1</i> gene variants display considerable variability. This study suggests that the pathogenic mechanism of <i>STAG1</i> gene variants may be linked to haploinsufficiency of the gene.</p>","PeriodicalId":35536,"journal":{"name":"遗传","volume":"48 2","pages":"227-235"},"PeriodicalIF":0.0,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146158312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
遗传Pub Date : 2026-02-20DOI: 10.16288/j.yczz.25-137
Cheng-Xi Liu, Wen-Wen Deng, Mei Long, Sheng-Zhi Yang, Xin-Feng Han, Cai-Wu Li, Ke Zhao, Li-Kou Zou
{"title":"Analysis of resistance and virulence genes in anaerobic <i>Escherichia coli</i> from giant pandas based on whole genome sequencing.","authors":"Cheng-Xi Liu, Wen-Wen Deng, Mei Long, Sheng-Zhi Yang, Xin-Feng Han, Cai-Wu Li, Ke Zhao, Li-Kou Zou","doi":"10.16288/j.yczz.25-137","DOIUrl":"10.16288/j.yczz.25-137","url":null,"abstract":"<p><p><i>Escherichia coli</i> is a facultative anaerobic bacterium frequently detected rate in the intestines of giant pandas. In this study, we isolated 169 anaerobic bacterial strains from fresh fecal samples of 13 giant pandas, including 13 strains of <i>E. coli</i>. Through whole-genome sequencing and analysis, we classified 13 <i>E. coli</i> strains into 9 distinct sequence types (STs), and identified 96 antibiotic resistance genes, 103 heavy metal resistance genes and 213 virulence genes. Notably, we observed the widespread presence of the <i>mdtA</i>, <i>mdtB</i>, <i>mdtC</i> and <i>cusA</i>, <i>cusB</i>, <i>cusC</i>, <i>cusF</i> gene in all <i>E. coli</i> isolates. Further genetic environment analysis revealed the presence of <i>baeS</i>/<i>baeR</i> upstream of <i>mdtABC</i>, a two-component system capable of regulating efflux pump expression to mediate resistance. The <i>cusABCF</i> operon was flanked by siderophore-related virulence genes (<i>fepA</i> and <i>entD</i>) upstream and the <i>cusS/cusR</i> regulatory system downstream. We also identified mobile genetic elements adjacent to these operons, which may facilitate the horizontal transfer of resistance and virulence determinants. This genome-based investigation systematically characterized antibiotic/metal resistance and virulence profiles in <i>E. coli</i> strains derived from giant panda, providing critical insights for safeguarding the health and welfare of this endangered species.</p>","PeriodicalId":35536,"journal":{"name":"遗传","volume":"48 2","pages":"213-226"},"PeriodicalIF":0.0,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146158359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
遗传Pub Date : 2026-02-20DOI: 10.16288/j.yczz.25-306
Jia-Yang Xue, Ze-Hui Chen, Wan-Jing Ping, Qiao-Mei Fu
{"title":"Ancient genomes reveal the genetic origins and social structure of the Shimao population.","authors":"Jia-Yang Xue, Ze-Hui Chen, Wan-Jing Ping, Qiao-Mei Fu","doi":"10.16288/j.yczz.25-306","DOIUrl":"10.16288/j.yczz.25-306","url":null,"abstract":"<p><p>Shimao site located at the pastoral-agricultural transition zone of northern Shaanxi, China, with its massive fortification systems and rich sacrificial remains, exemplifies the social complexity of an early state society. However, the origins of its population, social structure, and interactions with neighboring cultures have long been subjects of academic debate. To address these questions, a research team led by Qiaomei Fu from the Institute of Vertebrate Paleontology and Paleoanthropology of the Chinese Academy of Sciences, in collaboration with the Shaanxi Provincial Academy of Archaeology and other institutions, conducted a 13-year systematic study. They performed large-scale, systematic paleogenomic analyses on 169 ancient human skeletal remains from the core Shimao site, its peripheral settlements, and the southern Shanxi region. Breakthroughs were achieved in three key aspects. The study confirmed that the genetic composition of the Shimao population derived mainly from local Late Yangshao populations in northern Shaanxi, demonstrating genetic continuity with earlier local inhabitants. It also revealed close genetic affinities between the Shimao and Taosi populations in southern Shanxi, as well as significant genetic connections with steppe pastoralists associated with the Yumin culture and southern rice-farming communities. Most importantly, the study firstly and successfully reconstructed a four-generation family pedigree within the Shimao site, indicating that Shimao society was patrilineal and highly stratified. This study not only provides an unprecedented model for understanding the formation of early states in China but also offers direct genetic evidence for exploring power inheritance and social stratification in early East Asian states.</p>","PeriodicalId":35536,"journal":{"name":"遗传","volume":"48 2","pages":"119-127"},"PeriodicalIF":0.0,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146158395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
遗传Pub Date : 2026-02-20DOI: 10.16288/j.yczz.25-076
Zi-Hao Wang, Zhao-Qing Yang
{"title":"Advances in site-specific knock-in techniques for gene editing.","authors":"Zi-Hao Wang, Zhao-Qing Yang","doi":"10.16288/j.yczz.25-076","DOIUrl":"10.16288/j.yczz.25-076","url":null,"abstract":"<p><p>Gene-targeted knock-in technology serves as a cornerstone tool in genetic engineering and gene therapy, designed to circumvent the unpredictability and heterogeneityassociated with conventional random integration methods. However, its practical application has long been constrained by off-target activity and low efficiency during the editing process. Recent advances in site-specific recombinase systems (e.g., Bxb1 integrase) and programmable nuclease systems (e.g., CRISPR/Cas9) have significantly enhanced the precision and efficiency of gene knock-in. Notably, the Cas9-Bxb1 integrase system enables targeted integration of large DNA fragments (5-43 kb) into genomic safe harbor (GSH) sites, offering a transformative platform for disease modeling, functional genomics, and clinical therapeutics. This review systematically summarizes the progress of site-specific recombinase and nuclease systems, discusses GSH screening strategies and the role of multi-omics data in optimizing predictive models, and compares the strengths and limitations of twinPE+Bxb1 and PASTE systems. Future research should focus on developing novel integrases with low off-target activity, refining DSB-free editing technologies, and establishing cross-species GSH databases to advance applications in precision medicine and synthetic biology.</p>","PeriodicalId":35536,"journal":{"name":"遗传","volume":"48 2","pages":"128-141"},"PeriodicalIF":0.0,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146158751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
遗传Pub Date : 2026-02-20DOI: 10.16288/j.yczz.25-234
Yu-Jie Li, Fei-Fei Li, Wen-Qing Zhang, Qi Chen
{"title":"Mechanism of <i>tcirg1b</i> deficiency in disrupting central nervous system homeostasis of zebrafish.","authors":"Yu-Jie Li, Fei-Fei Li, Wen-Qing Zhang, Qi Chen","doi":"10.16288/j.yczz.25-234","DOIUrl":"10.16288/j.yczz.25-234","url":null,"abstract":"<p><p>Microglial phagocytosis is crucial for maintaining central nervous system (CNS) homeostasis, a process that depends on normal lysosomal acidification and is precisely regulated by vacuolar-type ATPase (V-ATPase). While mutations in the V-ATPase a3 subunit (encoded by the <i>tcirg1b</i> gene in zebrafish) are a major cause of human malignant osteopetrosis, the subunit's function in the CNS remains unknown. To investigate the role of the V-ATPase a3 subunit in the zebrafish CNS, we generated a <i>tcirg1b</i> knockout model. Although mutant zebrafish displayed no early neuronal defects, adult brains exhibited significant pathological alterations and behavioral abnormalities. Previous data showed that loss of <i>tcirg1b</i> resulted in enlarged microglia, suggesting potential functional alterations. In this study, transcriptome sequencing analysis of zebrafish macrophages revealed that phagosome formation and intracellular pH regulation pathway genes were significantly down-regulated. Functional analysis confirmed that V-ATPase a3 subunit deficiency impairs lysosomal acidification and digestive function in microglia, leading to the accumulation of apoptotic cell debris and TMR-dextran. Notably, specific restoration of <i>tcirg1b</i> expression in microglia successfully rescued the behavioral phenotypes of mutants, suggesting that the regulation of CNS homeostasis by the V-ATPase a3 subunit is primarily mediated through microglia. In summary, this study provides the first <i>in vivo</i> evidence that <i>tcirg1b</i> deficiency disrupts microglial function, thereby indirectly leading to an imbalance in CNS homeostasis. Our findings reveal a key role for the V-ATPase a3 subunit in regulating neural homeostasis and offer a new theoretical framework for studying the mechanisms of neurological diseases.</p>","PeriodicalId":35536,"journal":{"name":"遗传","volume":"48 2","pages":"201-212"},"PeriodicalIF":0.0,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146158415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}