Genes & development最新文献_第6页

LKB1 functions as a checkpoint for neuronal-glial balance during enteric nervous system development. 在肠神经系统发育过程中，LKB1作为神经元-胶质平衡的检查点。

IF 7.4 1区生物学

Genes & development Pub Date : 2026-08-03 DOI: 10.1101/gad.353358.125

Anthony Lucas, Florence Appaix, Jordan Allard, Marie Mével-Aliset, Anca G Radu, Florence Fauvelle, Bertrand Favier, Alexei Grichine, Jochen Maurer, Pierre Hainaut, Laura Attardi, Marc Billaud, Sakina Torch, Chantal Thibert

{"title":"LKB1 functions as a checkpoint for neuronal-glial balance during enteric nervous system development.","authors":"Anthony Lucas, Florence Appaix, Jordan Allard, Marie Mével-Aliset, Anca G Radu, Florence Fauvelle, Bertrand Favier, Alexei Grichine, Jochen Maurer, Pierre Hainaut, Laura Attardi, Marc Billaud, Sakina Torch, Chantal Thibert","doi":"10.1101/gad.353358.125","DOIUrl":"https://doi.org/10.1101/gad.353358.125","url":null,"abstract":"How the energy status of enteric progenitors controls neurogliogenesis and the subsequent formation of the complex enteric nervous system (ENS) remains poorly understood. We previously showed that the tumor suppressor kinase LKB1 is essential for postnatal ENS maintenance through amino acid homeostasis. Here, we investigated LKB1's functions during embryonic ENS formation using a genetically engineered mouse model with conditional Lkb1 inactivation in neural crest progenitors during gut colonization. Using advanced 3D imaging techniques on cleared tissue including light sheet microscopy and adaptive optics confocal microscopy, we found that Lkb1 loss impairs early neuronal differentiation followed by progressive glial degeneration, leading to hypoganglionosis and compromised digestive tissue integrity. Notably, Lkb1 inactivation induced a transient upregulation of the glial stress marker S100β during gestation, suggestive of a reactive glial state preceding glial loss. Consistent with this response, Lkb1 loss elevated oxidative stress in the digestive tract and in neural crest progenitors and their glial derivatives, triggering DNA damage and p53 activation. Although p53 ablation rescued glial specification in vitro and glial maintenance in vivo, it only partially restored ENS architecture in vivo without rescuing enteric neuron numbers. Together, these findings establish LKB1 as a critical metabolic checkpoint governing neuronal-glial balance during ENS development and suggest that dysregulated LKB1 signaling may contribute to human enteric neurogliopathies.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"40 15-16","pages":"1227-1249"},"PeriodicalIF":7.4,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148669046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Functional divergence of Capicua isoforms explains differential tissue vulnerability in neurological disease. Capicua亚型的功能分化解释了神经系统疾病中组织易感性的差异。

IF 7.4 1区生物学

Genes & development Pub Date : 2026-08-03 DOI: 10.1101/gad.353596.125

Hamin Lee, Esmeralda Villavicencio Gonzalez, Elias M Rivera, Mark A Durham, Ronald Richman, Elizabeth H-Y Chu, Kailey Xia, Hu Chen, Zhandong Liu, Surabi Veeraragavan, Binoy Shivanna, Huda Y Zoghbi

{"title":"Functional divergence of Capicua isoforms explains differential tissue vulnerability in neurological disease.","authors":"Hamin Lee, Esmeralda Villavicencio Gonzalez, Elias M Rivera, Mark A Durham, Ronald Richman, Elizabeth H-Y Chu, Kailey Xia, Hu Chen, Zhandong Liu, Surabi Veeraragavan, Binoy Shivanna, Huda Y Zoghbi","doi":"10.1101/gad.353596.125","DOIUrl":"10.1101/gad.353596.125","url":null,"abstract":"Many neurological diseases impact specific brain regions despite widespread expression of the disease-related protein. Spinocerebellar ataxia type 1 (SCA1) primarily affects the cerebellum, though Ataxin-1 (ATXN1) is widely expressed. We previously showed that intensified interaction between mutant ATXN1 and Capicua (CIC) drives SCA1 pathogenesis in the cerebellum, whereas ATXN1 loss augments amyloid β production in the hippocampus and cortex. CIC, however, forms a complex with ATXN1 and its paralog, Ataxin-1-like (ATXN1L), yet knockout of either yields completely different phenotypes. To determine whether this could be due to CIC having two isoforms, we generated mice bearing either the long (CIC-L) or short (CIC-S) isoform. Loss of CIC-L led to cognitive deficits, whereas loss of CIC-S caused early postnatal lethality, phenocopying ATXN1 and ATXN1L knockout mice, respectively. Furthermore, CIC-L preferentially interacts with ATXN1, and CIC-S with ATXN1L. Our data underscore the importance of isoform-paralog interplay in studying regional vulnerability in neurodegenerative diseases.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"1267-1282"},"PeriodicalIF":7.4,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13390769/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148535806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dual regulation of the unfolded protein response by IGF2BP3 during ER stress. 内质网应激中IGF2BP3对未折叠蛋白反应的双重调控。

IF 7.4 1区生物学

Genes & development Pub Date : 2026-08-03 DOI: 10.1101/gad.353291.125

Aleksandra S Anisimova, Sabina Omerbegovic, Milica Mihailovic, Sascha Gratzl, Harald Hornegger, Irmgard Fischer, Gijs A Versteeg, Stefan L Ameres, G Elif Karagöz

{"title":"Dual regulation of the unfolded protein response by IGF2BP3 during ER stress.","authors":"Aleksandra S Anisimova, Sabina Omerbegovic, Milica Mihailovic, Sascha Gratzl, Harald Hornegger, Irmgard Fischer, Gijs A Versteeg, Stefan L Ameres, G Elif Karagöz","doi":"10.1101/gad.353291.125","DOIUrl":"10.1101/gad.353291.125","url":null,"abstract":"Misfolded protein accumulation in the endoplasmic reticulum (ER) perturbs cellular homeostasis, causing pathological ER stress. While a transcriptional response is paramount for the unfolded protein response (UPR), which counters ER protein stress, multiple UPR-linked mRNAs are posttranscriptionally regulated. However, the mechanisms mediating this regulation remain unclear. Here, we reveal specific interactions between the conserved RNA-binding protein IGF2BP3 and transcripts encoding UPR effectors. During ER stress, IGF2BP3 destabilizes many of its target transcripts, including UPR effectors. Mechanistically, ER stress enhances IGF2BP3's association with the mRNA decapping complex and the ER stress sensor RNase IRE1, which correlates with a shift toward mRNA destabilization. Unexpectedly, prolonged depletion of IGF2BP3 inhibits the UPR via decreased transcription of UPR target genes. Together, our findings suggest that IGF2BP3 contributes to proteostasis during ER stress through a dual mechanism: directly promoting mRNA degradation to reduce translation and folding burden and indirectly supporting transcriptional activation of the UPR.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"1304-1329"},"PeriodicalIF":7.4,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13431160/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148578210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

PWWP mutants of the transcriptional cofactor JASPer divert promoter and enhancer activities and suppress position effect variegation in Drosophila. 在果蝇中，转录辅助因子JASPer的PWWP突变体转移启动子和增强活性，抑制位置效应变异。

IF 7.4 1区生物学

Genes & development Pub Date : 2026-08-03 DOI: 10.1101/gad.353541.125

Derek Atkinson, Karolina Barucka, Lisa Jerabek, Francesco Cardamone, Yinxiu Zhan, Lisa Kolodziejczyk, Catherine Regnard, Nicola Iovino, Gunter Reuter, Thomas Jenuwein

{"title":"PWWP mutants of the transcriptional cofactor JASPer divert promoter and enhancer activities and suppress position effect variegation in Drosophila.","authors":"Derek Atkinson, Karolina Barucka, Lisa Jerabek, Francesco Cardamone, Yinxiu Zhan, Lisa Kolodziejczyk, Catherine Regnard, Nicola Iovino, Gunter Reuter, Thomas Jenuwein","doi":"10.1101/gad.353541.125","DOIUrl":"10.1101/gad.353541.125","url":null,"abstract":"Su(var) genes regulate the formation and maintenance of heterochromatin in Drosophila melanogaster, yet how factors associated with active chromatin influence heterochromatin stability remains poorly understood. Through a new genetic Su(var) screen, we identified two strong suppressors of position effect variegation that remain epistatic to increased Su(var)3-9 dosage in the In(1)w m4h rearrangement. Both mutations affect the PWWP domain of the transcriptional cofactor JASPer, previously implicated in safeguarding transcription within euchromatin. In nuclear cycle (NC14) mutant embryos carrying these mutations, canonical heterochromatic marks (H3K9me2/3) are reduced, while activating histone modifications (H3K4me1 and H3K27ac) accumulate at heterochromatin regions. Whereas wild-type JASPer localizes predominantly to H3K36me3-enriched gene bodies, the mutant protein (JASPerSu140) shows reduced chromatin-association and it is redistributed to cis-regulatory elements. Notably, a subset of developmentally regulated enhancers, including the white enhancer, becomes enriched for JASPerSu140 and display elevated enhancer-RNAs transcription at NC14 embryos. Consistent with these molecular changes, mutant embryos exhibit partial decompaction of the heterochromatin domain containing the In(1)w m4h rearrangement and activation of satellite repeat transcription. Together, our findings identify JASPer as a previously unrecognized Su(var) factor and reveal that proper partitioning between euchromatin and heterochromatin domains is critical for maintaining position effect variegation.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"1330-1349"},"PeriodicalIF":7.4,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148470109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Metabolic adaptations of the tumor macroenvironment and their role in cancer progression and survivorship. 肿瘤宏观环境的代谢适应及其在癌症进展和生存中的作用。

IF 7.4 1区生物学

Genes & development Pub Date : 2026-08-03 DOI: 10.1101/gad.353830.126

Devesh Raizada, Ana P Gomes

{"title":"Metabolic adaptations of the tumor macroenvironment and their role in cancer progression and survivorship.","authors":"Devesh Raizada, Ana P Gomes","doi":"10.1101/gad.353830.126","DOIUrl":"10.1101/gad.353830.126","url":null,"abstract":"Cancer progression is shaped not only by tumor-intrinsic programs and the local microenvironment but also by profound metabolic rewiring of the host at the organismal scale. Tumors engage in dynamic cross-talk with distant organs, immune and neuroendocrine networks, and systemic nutrient pools, generating a metabolically permissive macroenvironment that fuels tumor growth, supports metastatic dissemination, and undermines therapeutic efficacy. In this review, we synthesize emerging evidence showing how cancer-driven systemic metabolic remodeling reshapes glucose, lipid, and protein metabolism, perturbs immune and hematopoietic homeostasis, and hijacks neuroendocrine circuits governing energy balance and stress responses. We further highlight how these adaptations fuel cellular energetics within tumor cells as well as promote premetastatic niche formation, immune evasion, and therapy resistance, while leaving durable metabolic and inflammatory scars that accelerate biological aging and compromise long-term health in cancer survivors. Together, these findings position tumor-host metabolic cross-talk as a central, targetable axis in cancer biology with broad implications for therapy and survivorship care.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"1178-1201"},"PeriodicalIF":7.4,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13431171/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148470111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Isoform-paralog specificity and tissue-dependent vulnerabilities in neurological disorders. 神经系统疾病的异构体平行特异性和组织依赖性脆弱性。

IF 7.4 1区生物学

Genes & development Pub Date : 2026-08-03 DOI: 10.1101/gad.353864.126

Karina Hernandez-Quijada, Kenneth Y Kwan

引用次数: 0

Coordination of nuclear RNA processing by speckle-localized kinase TAOK2. 斑点定位激酶TAOK2对核RNA加工的协调作用。

IF 7.4 1区生物学

Genes & development Pub Date : 2026-08-03 DOI: 10.1101/gad.353395.125

Bridget E Begg, Matthew A Tracey, Shengyan Gao, Svetlana Earnest, Mohd Altaf Najar, George M Burslem, Melanie H Cobb, Beatriz M A Fontoura, Kristen W Lynch

{"title":"Coordination of nuclear RNA processing by speckle-localized kinase TAOK2.","authors":"Bridget E Begg, Matthew A Tracey, Shengyan Gao, Svetlana Earnest, Mohd Altaf Najar, George M Burslem, Melanie H Cobb, Beatriz M A Fontoura, Kristen W Lynch","doi":"10.1101/gad.353395.125","DOIUrl":"10.1101/gad.353395.125","url":null,"abstract":"Nuclear speckles are membraneless organelles that act as active splicing hubs especially at sites of high transcription. Emerging views of this dynamic subnuclear structure place it as a hub of RNA processing, impacting steps from transcription to nuclear export. To manage this complex microcosm of RNA metabolism, phosphorylation by kinases is required for nuclear speckles to execute their functions. The nuclear speckle-localized kinase, TAOK2, mediates the splicing and export of viral transcripts at the nuclear speckle, but its role in the processing of cellular transcripts was unknown. We used siRNA knockdown of TAOK2 and assessed RNA transcripts in both whole-cell and nucleocytoplasmic fractions to characterize the complete endogenous effects of TAOK2. We found that TAOK2 knockdown impacts >10% of the transcriptome, through changes in alternative splicing, nuclear export, and transcript abundance. Cellular and biochemical phosphoproteomics further revealed nuclear speckle scaffolding proteins SRRM1 and SRRM2 as potential direct phosphorylation targets of TAOK2, mediating its large effects on speckle integrity and speckle-localized splicing. Indeed, knockdown of TAOK2 perturbs almost all speckle-resident serine/arginine (SR)-rich proteins while leaving heterogeneous ribonucleoproteins unperturbed. Altogether, we propose that phosphorylation of SRRM1/2 by TAOK2 plays a structural maintenance role that impacts SR protein-driven exon inclusion at the nuclear speckle.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"1250-1266"},"PeriodicalIF":7.4,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13374701/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148445645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Bcl11-Cxxc1 axis regulates stage-specific chromatin accessibility during lymphocyte development. Bcl11-Cxxc1轴调节淋巴细胞发育过程中特定阶段染色质的可及性。

IF 7.4 1区生物学

Genes & development Pub Date : 2026-08-03 DOI: 10.1101/gad.353082.125

Kazuki Okuyama, Wooseok Seo, Hirotaka Takahashi, Sawako Muroi, Ning Hou, Shinsuke Ito, Tatsuya Sawasaki, Haruhiko Koseki, Yibo Wu, Ichiro Taniuchi

引用次数: 0

Greg Hannon: the scientist who changed biology, and the people who practiced it. 格雷格·汉农：改变生物学的科学家，以及从事生物学研究的人。

IF 7.4 1区生物学

Genes & development Pub Date : 2026-08-03 DOI: 10.1101/gad.354062.126

Camila O Dos Santos

引用次数: 0

STK38/L promote tissue growth and cancer by inhibiting the Hippo pathway. STK38/L通过抑制Hippo通路促进组织生长和肿瘤。

IF 7.4 1区生物学

Genes & development Pub Date : 2026-07-01 DOI: 10.1101/gad.353309.125

Jeongmin An, Zhen Huang, Amrutha Kizhedathu, Tian Lan, Tzuling Lin, Hyejin Joo, Eshan Malinda Thilakaratne, Yuhan Liu, Yun Yi Xu, Bing Yang, Pablo Lara-Gonzalez, Rahul Warrior, Ray Luo, Wenqi Wang

{"title":"STK38/L promote tissue growth and cancer by inhibiting the Hippo pathway.","authors":"Jeongmin An, Zhen Huang, Amrutha Kizhedathu, Tian Lan, Tzuling Lin, Hyejin Joo, Eshan Malinda Thilakaratne, Yuhan Liu, Yun Yi Xu, Bing Yang, Pablo Lara-Gonzalez, Rahul Warrior, Ray Luo, Wenqi Wang","doi":"10.1101/gad.353309.125","DOIUrl":"10.1101/gad.353309.125","url":null,"abstract":"The Hippo pathway is a key regulator of development, regeneration, tissue homeostasis, and organ size, and its dysregulation promotes tumorigenesis. However, the precise mechanisms of its regulation in both normal physiology and cancer remain incompletely understood. Here, we identify STK38 and STK38L (also known as NDR1 and NDR2), previously proposed as redundant kinases of LATS, as negative regulators of the Hippo pathway. STK38/L inhibit LATS by competitively binding to MOB1 and disrupting the LATS-MOB1 complex, a process independent of their kinase activity. This inhibitory mechanism is evolutionarily conserved, as the Drosophila ortholog Tricornered similarly impairs Warts-Mats complex formation, resulting in enlarged fly wing size. Pathologically, STK38L is highly expressed in ovarian cancer and required for ovarian tumor growth, and its amplification correlates with YAP activation and increased tumor sensitivity to TEAD inhibitors. Taken together, our study reveals a conserved role of STK38/L in Hippo pathway regulation, providing new insights into Hippo-dependent growth control and cancer development.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"1080-1098"},"PeriodicalIF":7.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147928495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0