Xiuxia Zhou,Krithika S. Rao,Sruti Shiva,Catharina van Heusden,Qi Wei,Nobuhiko Fukuda,Mayoko Tsuji,Angelina Kendi,Laura R. Bradley,Jinming Zhao,John B. Trudeau,Anuradha Ray,Richard C. Boucher,Sally E. Wenzel
{"title":"Mitochondrial metabolic dysfunction in airway epithelial cells promotes goblet cell metaplasia and more severe asthma","authors":"Xiuxia Zhou,Krithika S. Rao,Sruti Shiva,Catharina van Heusden,Qi Wei,Nobuhiko Fukuda,Mayoko Tsuji,Angelina Kendi,Laura R. Bradley,Jinming Zhao,John B. Trudeau,Anuradha Ray,Richard C. Boucher,Sally E. Wenzel","doi":"10.1172/jci200067","DOIUrl":"https://doi.org/10.1172/jci200067","url":null,"abstract":"Type 2 (T2) inflammation is a defining feature of asthma and associated with epithelial dysfunction, including goblet cell metaplasia and ciliary loss. Here, we investigated whether T2 inflammation and associated 15 lipoxygenase-1 (15LO1) activity alters mitochondrial metabolism in airway epithelial cells (AECs) and contributes to disease pathophysiology. Freshly isolated AECs from T2-high asthmatic participants exhibited increased oxygen consumption rates (OCR), including elevated basal respiration and proton leak, alongside reduced coupling efficiency compared to T2-low participants. These functional changes were accompanied by increased expression of electron transport chain (ETC) proteins, worse lung function and epithelial phenotypic changes. In vitro , IL-13 stimulation of differentiated AECs recapitulated these findings, inducing higher OCR, increased ETC protein levels, and enhanced proton leak while paradoxically reducing intracellular ATP. These metabolic alterations are associated with increased uncoupling protein 2 (UCP2) expression and goblet cell differentiation. Mechanistically, 15LO1 emerged as a key regulator, as ALOX15 knockdown or pharmacologic inhibition reduced OCR parameters, ETC protein expression, UCP2, and goblet cell markers, without effect on ATP levels, suggesting additional regulatory mechanisms. Collectively, these findings identify a metabolic axis linking T2 inflammation, mitochondrial dysfunction, and airway epithelial metabolism, while highlighting 15LO1-driven mitochondrial uncoupling as a potential therapeutic target in asthma. ","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"18 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088888","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}
Katrine N. Madsen,Soki Kashima,Hanna Soulati,Lena Wirth,Katsuhiro Ito,Zachary A. Yochum,Vivien Moritz,Julia Walker,Marc Machaalani,Fady Ghali,Patrick Kenney,Adebowale Adeniran,Michael Hurwitz,Toni K. Choueiri,David A. Braun
{"title":"Pharmacologic HIF-2α inhibition preserves T cell effector function in clear cell renal cell carcinoma","authors":"Katrine N. Madsen,Soki Kashima,Hanna Soulati,Lena Wirth,Katsuhiro Ito,Zachary A. Yochum,Vivien Moritz,Julia Walker,Marc Machaalani,Fady Ghali,Patrick Kenney,Adebowale Adeniran,Michael Hurwitz,Toni K. Choueiri,David A. Braun","doi":"10.1172/jci204613","DOIUrl":"https://doi.org/10.1172/jci204613","url":null,"abstract":"Hypoxia-inducible factor 2α (HIF-2α) is a central oncogenic driver in clear cell renal cell carcinoma (ccRCC) and a therapeutic target of the small-molecule inhibitor belzutifan. Genetic studies in murine models have suggested that hypoxia signaling may support T cell effector programs, raising concern that HIF-2α inhibition could impair antitumor immunity. However, whether pharmacologic HIF-2α inhibition alters human T cell biology remains unknown. Here, we investigated the cell-intrinsic effects of EPAS1 (encoding HIF-2α) perturbation in primary human T cells. CRISPR/Cas9-mediated deletion of HIF-2α demonstrated no notable transcriptional effects. Similarly, pharmacologic treatment with belzutifan produced minimal transcriptional changes and did not impair proliferation, cytokine production, polyfunctionality, or cytotoxic activity in T cells derived from healthy donor peripheral blood, peripheral blood from patients with ccRCC, or tumor-infiltrating lymphocytes under hypoxic conditions. High- dimensional immunophenotyping revealed preserved T cell differentiation and activation states following pharmacologic HIF-2α inhibition in vitro and in peripheral blood from patients receiving HIF-2α inhibitor therapy. Together, these findings demonstrate that pharmacologic HIF-2α inhibition preserves key effector programs, providing a mechanistic basis for the immunologic safety of HIF-2α–targeted therapy in ccRCC.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"81 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088885","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}
Rameen Jamil,Sanja Huibner,Ping Yang,James Nnamutete,Jodie L. White,Lori Sokoll,James Pollock,Margaret Nakalanzi,Simon Peter Bukenya,Stephen D. Kiboneka,Mathias Agaba,Mary J. Nalubowa,Aggrey Anok,Godfrey Kigozi,Ronald M. Galiwango,Bryan Coburn,Cindy M. Liu,Jessica L. Prodger,Aaron A.R. Tobian,Rupert Kaul
{"title":"Impact of sexual debut on urethral immunology and microbiome in adolescent males from Rakai, Uganda","authors":"Rameen Jamil,Sanja Huibner,Ping Yang,James Nnamutete,Jodie L. White,Lori Sokoll,James Pollock,Margaret Nakalanzi,Simon Peter Bukenya,Stephen D. Kiboneka,Mathias Agaba,Mary J. Nalubowa,Aggrey Anok,Godfrey Kigozi,Ronald M. Galiwango,Bryan Coburn,Cindy M. Liu,Jessica L. Prodger,Aaron A.R. Tobian,Rupert Kaul","doi":"10.1172/jci208629","DOIUrl":"https://doi.org/10.1172/jci208629","url":null,"abstract":"BACKGROUND. The penile urethra is a primary site of HIV acquisition in males, although little is known about the urethral determinants of HIV susceptibility. Inflammation at other genital sites enhances HIV risk, and studies suggest that some inflammatory urethral bacteria may be vaginally acquired. Here, we characterize the impact of sexual debut on the microbiome and immune milieu of the penile urethra in adolescent males from Rakai, Uganda. METHODS. A cohort of 185 self-reported sexually naïve adolescent males from Rakai, Uganda were followed longitudinally for 3 years, with questionnaires administered every 3 months and urethral swabs collected annually. Urethral soluble immune factors were quantified by chemiluminescent multiplex immunoassay and bacterial 16S rRNA sequencing was performed. Unsupervised clustering and mixed-effects models were used to assess associations between sexual debut and the urethral microbiome and immune milieu. RESULTS. Unsupervised clustering at 36 months identified two distinct urethral Community State Types (CSTs): CST-1 was dominated by Streptococcus mitis and CST-2 by bacteria associated with bacterial vaginosis (BV), particularly Sneathia amnii and Gardnerella vaginalis . CST-2 was greatly enriched at 36 months compared to baseline and was associated strongly with sexual debut. Individual bacterial taxa enriched in CST-2 were associated with both sexual debut and elevated urethral inflammatory cytokines, independent of serum testosterone and penile circumcision status. CONCLUSION. The penile urethra is colonized by BV-associated bacteria after penile-vaginal sex debut. Their presence in the urethra induces local inflammation and may serve as a reservoir for subsequent reintroduction into the vagina of female sexual partners.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"18 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149092037","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}
Kaylan M.L. Burns,Mashiat Zaman,Daniel Young,Michelle Hua,Yu-Yun Gao,Yvonne Yan Yan Or,Farzaneh Nobakht,Bryn D. Webb,Julie A. Jurgens,Francis Ramond,Xing-Chang Wei,Caroline D. Robson,Alistair T. Pagnamenta,Marvel Megaly,Belal Tafech,Antoine Dufour,Timothy E. Shutt,Ping Yee Billie Au,Guang Yang
{"title":"Nucleocytoplasmic shuttling of USP15 promotes pathological autophagy that disrupts neural stem cell homeostasis and neurodevelopment","authors":"Kaylan M.L. Burns,Mashiat Zaman,Daniel Young,Michelle Hua,Yu-Yun Gao,Yvonne Yan Yan Or,Farzaneh Nobakht,Bryn D. Webb,Julie A. Jurgens,Francis Ramond,Xing-Chang Wei,Caroline D. Robson,Alistair T. Pagnamenta,Marvel Megaly,Belal Tafech,Antoine Dufour,Timothy E. Shutt,Ping Yee Billie Au,Guang Yang","doi":"10.1172/jci196452","DOIUrl":"https://doi.org/10.1172/jci196452","url":null,"abstract":"During organogenesis, stem cells undergo cellular and metabolic remodelling, facilitated by autophagy-mediated turnover of organelles. Autophagy impairment has been linked to human diseases, including neurodevelopmental disorders associated with disrupted neural stem/precursor cell (NPC) homeostasis, but the underlying mechanisms and pathogenic processes governing these connections remain poorly understood. Here, we report three de novo variants of uncertain significance (p.Gly223Asp, p.Gly889Glu, p.Met978Val) in the deubiquitinase USP15 in human probands with diverse clinical features, including a spectrum of brain malformations and metabolic phenotypes. Proband variants differentially altered USP15 activity and nucleocytoplasmic localization. USP15 showed dynamic localization in NPCs of embryonic mouse cerebral cortex. Using a knock-in mouse model carrying the p.Met978Val variant, we showed that aberrant cytoplasmic accumulation of USP15, but not its loss-of-function, impaired NPC self-renewal and differentiation, leading to reduced neuronal output and enlarged lateral ventricles. Mechanistically, USP15 deubiquitinated autophagy regulator ATG16L1, impeded its normal turnover, and impaired autophagy. Concurrently, lipid droplet mobilization and mitochondrial dynamics were attenuated. Reestablishing the ubiquitination-deubiquitination balance restored autophagy activity and normal neurogenesis. Our findings suggest that nucleocytoplasmic shuttling of USP15 creates a switch-like autophagy signal controlling NPC homeostasis, and its disruption may contribute to the pathogenesis of complex neurodevelopmental conditions.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"36 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088883","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}
Jyoti Chhimwal,Sonal Sinha,Jina Kim,Mario Alba,Lucía Barbier-Torres,Jiaohong Wang,Heping Yang,Youngyi Lim,Ramachandran Murali,Maria Lauda Tomasi,Sungyong You,José M. Mato,Shelly C. Lu
{"title":"Nuclear prohibitin 1 depletion drives alcohol-associated liver injury and sensitization to colon cancer liver metastasis","authors":"Jyoti Chhimwal,Sonal Sinha,Jina Kim,Mario Alba,Lucía Barbier-Torres,Jiaohong Wang,Heping Yang,Youngyi Lim,Ramachandran Murali,Maria Lauda Tomasi,Sungyong You,José M. Mato,Shelly C. Lu","doi":"10.1172/jci206235","DOIUrl":"https://doi.org/10.1172/jci206235","url":null,"abstract":"Alcohol-associated liver disease (ALD) is associated with higher incidence of colorectal liver metastasis (CRLM); prohibitin 1 (PHB1) defends against CRLM yet its role in ALD and ALD-CRLM is poorly understood and was investigated here. In human, murine, and in vitro ALD models, cytosolic and nuclear PHB1 were depleted, whereas mitochondrial PHB1 was preserved despite a loss in mitochondrial mass. Nuclear PHB1 loss was driven by CRM1-mediated export, and blocking this interaction with a PHB1 nuclear export signal (NES) peptide retained nuclear PHB1, ameliorating both ALD and ALD-CRLM. PHB1 NES prevented depletion of nuclear methionine adenosyltransferase α1, oxidative stress, and induction of matrix metalloproteinase 7 (MMP-7) and multiple oncogenes. Single-nucleus RNA sequencing of NIAAA diet-fed mouse livers and spatial transcriptomics of ALD-CRLM mice livers revealed that PHB1 NES treatment mitigated alcohol-induced metabolic and oncogenic stress, attenuated pro-inflammation and pro-fibrogenic responses, remodeled immunosuppressive microenvironment and contributed to overall hepatoprotection. These findings identify nuclear PHB1 depletion as a driver and a promising therapeutic target in ALD and ALD-CRLM.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088884","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}
Patrick T. Gauthier,Louisa M.S. Gerhardt,Lorenz Jahn,Christian Hinze,Philip F. Halloran
{"title":"Digital cytometry of leukocyte landscapes reveals shared correlates of rejection across organ transplants","authors":"Patrick T. Gauthier,Louisa M.S. Gerhardt,Lorenz Jahn,Christian Hinze,Philip F. Halloran","doi":"10.1172/jci208686","DOIUrl":"https://doi.org/10.1172/jci208686","url":null,"abstract":"Background. Improved understanding of the cellular mechanisms of organ transplant rejection is needed for developing targeted therapies to improve outcomes. We used digital cytometry to estimate the digital leukocyte entities (DLE) shared by rejection in biopsies of kidney, heart, lung, and liver organ transplants. Methods. We used CIBERSORTx with the LM22 leukocyte reference to estimate associations between 22 DLEs with rejection in 8422 transplant biopsies - 4898 kidney, 2361 heart, 652 lung, and 538 liver. Results. In all organs, rejection correlated with an increase in DLEs designated as classically activated macrophages and a decrease in DLEs designated regulatory T cells. T cell-mediated rejection (TCMR) was associated with a massive increase in otherwise rare T cell DLEs designated memory-activated CD4 and Tγδ, as well as follicular-helper CD4 and CD8. TCMR also had increased DLE designated plasma cells, compatible with a role for the B cell lineage in antigen presentation in TCMR. Antibody-mediated rejection (ABMR) in kidney and heart transplant biopsies correlated with increased DLEs representing activated mast cells, activated NK cells, and monocytes. Some findings were validated by single-cell/nucleus RNAseq data from kidney and liver biopsies. Conclusion. The shared correlations of DLEs with rejection in all organs - e.g. CD4ma with TCMR and activated mast cells with ABMR - suggest novel aspects of rejection. These findings can guide the search for the in vivo leukocytes that correspond with the digital entities, with potential clinical applications. Trial registration. ClinicalTrials.gov NCT01299168, NCT02670408, NCT02812290, NCT03193151. Funding. Genome Canada and a grant from Natera, Inc.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"28 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149020349","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}
Wanhai Qin,Wayne Brailsford,Stacey M. Cromer Berman,Christina S Thornton,Antonio DiGiandomenico,Paul Kubes
{"title":"Targeting virulence factors Psl and PcrV restores host defense in bronchiectasis and cystic fibrosis models","authors":"Wanhai Qin,Wayne Brailsford,Stacey M. Cromer Berman,Christina S Thornton,Antonio DiGiandomenico,Paul Kubes","doi":"10.1172/jci205523","DOIUrl":"https://doi.org/10.1172/jci205523","url":null,"abstract":"Chronic Pseudomonas aeruginosa infection is a central driver of bronchiectasis and contributes to progressive lung decline in patients with cystic fibrosis (CF), even in the era of CFTR modulators. A major limitation in the field is that conventional mouse models fail to develop persistent, biofilm-associated lung infection, restricting mechanistic studies and preclinical evaluation. Here, we establish clinically relevant infection models by combining CF-like mouse strains (βENaC-overexpressing and CFTR-deficient mice) with agarose bead–embedded P . aeruginosa that forms persistent, tobramycin-refractory biofilms. Using intravital lung microscopy, we show that alveolar macrophages initially respond by surrounding biofilms but progressively dissociate from the biofilms during persistent infection. Neutrophils are also recruited but fail to clear bacteria. Administration of gremubamab (MEDI3902), a bispecific antibody targeting the virulence factors Psl and PcrV, preserves alveolar macrophages in persistent biofilm infection, restores bacterial sensing and phagocytosis, limits excessive neutrophilic inflammation, and significantly improves bacterial clearance and survival. Together, these findings establish a clinically relevant persistent P. aeruginosa infection model and highlight gremubamab as a promising virulence-targeted therapy to potentially overcome bacterial immune evasion while restoring host defense in mouse models of bronchiectasis and CF.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149020348","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}
Yumeng Zhang,Pernelle Pulh,Michelle F. Pan,Yi He,Juanzhu Yan,Annie Li,Renée M. McKay,Lu Q. Le
{"title":"KROX20 marks sebaceous gland stem cells and regulates their differentiation to maintain skin oil balance","authors":"Yumeng Zhang,Pernelle Pulh,Michelle F. Pan,Yi He,Juanzhu Yan,Annie Li,Renée M. McKay,Lu Q. Le","doi":"10.1172/jci206364","DOIUrl":"https://doi.org/10.1172/jci206364","url":null,"abstract":"Oil-producing sebaceous glands (SGs), attached to the upper/ middle portion of hair follicles, are indispensable for maintaining skin hydration, and their dysfunction leads to dry skin. However, the molecular mechanisms underlying regulation of SG stem cells remain largely unknown. We identified transcription factor KROX20 as a marker of SG stem cells that sustains their stemness throughout SG morphogenesis and homeostasis. We developed an inducible mouse model in which ablation of KROX20-positive cells causes SG loss and rapidly and robustly induces dry, flaky, alopecia symptoms following induction. This model, termed Xeroflacia (Xero = xerosis, fla = flaky, cia = alopecia), provides a tool for studying the biology of dry skin. Furthermore, we found that KROX20 directly regulates Notch1 transcription to orchestrate the balance between SG stem cell self-renewal and differentiation. Small molecule drug modulation of Notch1 signaling to activate or inhibit the pathway enabled us to regulate SG differentiation to maintain skin oil levels, providing a proof-of-principle that other signaling pathways downstream of Krox20 could be potential therapeutic targets for sebaceous gland-related diseases.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"222 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149020347","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}
Phan Q. Duy,Benjamin C. Reeves,Huanxing Sun,Xueyan Peng,Pazhanichamy Kalailingam,Garrett Allington,Evan Dennis,Le Thi Hao,Lei Wang,David Rufino-Ramos,Shujuan Zhao,Qiang Li,Neel H. Mehta,William C. Davalan,Mason Blacker,Anthony J. Piscopo,Shozeb Haider,Baojian Fan,Kedous Y. Mekbib,Shuai Shao,Carol Nelson-Williams,TuKiet T. Lam,Benjamin P. Kleinstiver,Patricia L. Musolino,Seth L. Alper,Sheng Chih Jin,Erica L. Herzog,Kristopher T. Kahle
{"title":"Microglial GRB2 is essential for brain ventriculogenesis and CSF homeostasis","authors":"Phan Q. Duy,Benjamin C. Reeves,Huanxing Sun,Xueyan Peng,Pazhanichamy Kalailingam,Garrett Allington,Evan Dennis,Le Thi Hao,Lei Wang,David Rufino-Ramos,Shujuan Zhao,Qiang Li,Neel H. Mehta,William C. Davalan,Mason Blacker,Anthony J. Piscopo,Shozeb Haider,Baojian Fan,Kedous Y. Mekbib,Shuai Shao,Carol Nelson-Williams,TuKiet T. Lam,Benjamin P. Kleinstiver,Patricia L. Musolino,Seth L. Alper,Sheng Chih Jin,Erica L. Herzog,Kristopher T. Kahle","doi":"10.1172/jci185791","DOIUrl":"https://doi.org/10.1172/jci185791","url":null,"abstract":"Microglia play essential yet poorly understood roles in brain development, including axon guidance, regulation of neurogenesis, and pruning of neuronal projections. Congenital hydrocephalus (CH), characterized by enlarged cerebrospinal fluid (CSF)-filled ventricles, is a leading cause of pediatric brain surgery, but its molecular mechanisms remain unclear. We have identified what we believe to be novel, recurrent, damaging missense variants in the SH3-binding domain of the adaptor protein Growth Factor Receptor-Bound Protein 2 ( GRB2 ) in unrelated patients with CH. GRB2 is significantly co-expressed with one of its known upstream receptor tyrosine kinase partners, CSF1R, in the developing human brain, particularly in a microglial subtype associated with regulation of neural stem cells. Immunoprecipitation validated GRB2-CSF1R binding in mouse microglial cells and human monocyte cell line. Cx3cr1-Grb2 fl/fl mice engineered with conditional deletion of Grb2 in microglia exhibit congenital absence of microglia and early postnatal severe communicating (non-obstructive) hydrocephalus, mimicking GRB2 -mutant patients. The severe ventriculomegaly of Cx3cr1-Grb2 fl/fl mice is associated with both depletion of cerebral cortical neurons and impairment of glia-lymphatic-mediated CSF flow. Together, these findings implicate a role of GRB2 in microglia that could be essential for brain development and CSF homeostasis.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"172 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148923220","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}
Yan Yin,Emily Y. So,Eliana Wolf,Vivian Robles Pinos,Meade Haller,Renjie Shang,Sylvia C. Hewitt,Alex Tak,Brent M. Bany,David Y. Chen,Mengcheng Shen,Francesco J. DeMayo,Liang Ma
{"title":"Retinoic acid receptor signaling orchestrates uterine receptivity, decidual competence, and immune homeostasis during early pregnancy","authors":"Yan Yin,Emily Y. So,Eliana Wolf,Vivian Robles Pinos,Meade Haller,Renjie Shang,Sylvia C. Hewitt,Alex Tak,Brent M. Bany,David Y. Chen,Mengcheng Shen,Francesco J. DeMayo,Liang Ma","doi":"10.1172/jci206283","DOIUrl":"https://doi.org/10.1172/jci206283","url":null,"abstract":"Successful implantation requires precise coordination of uterine epithelial receptivity, stromal decidualization, and immune homeostasis during a narrow peri-implantation window. Although retinoic acid (RA) signaling has been implicated in female reproduction, the endogenous and isoform-specific roles of retinoic acid receptors (RARs) remain poorly defined. Here, we combined isoform-specific genetic mouse models, transcriptomic profiling, and functional studies in mouse and human stromal cells to determine how RAR signaling regulates early pregnancy. We found that RARG is the dominant RAR isoform required for female fertility in mice, as its deletion severely impaired implantation, whereas combined loss of all RAR isoforms caused complete reproductive failure. RAR deficiency disrupted multiple sequential reproductive processes, including sperm transport and fertilization, suppression of uterine estrogen receptor activity, acquisition of stromal decidualization competence, and maintenance of uterine immune homeostasis. Transcriptomic analyses identified conserved epithelial and mesenchymal programs altered across independent RAR-deficient mouse models and revealed significant overlap with endometrial gene signatures from women with recurrent implantation failure. In human endometrial stromal cells, suppression of the RARA isoform consistently disrupted decidualization across three independent primary cell lines and an immortalized cell model. Together, these findings identify RAR signaling as a critical regulator of early pregnancy and reveal conserved, isoform-specific functions required for early pregnancy.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"77 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148923221","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}
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