Heterozygous germline mutations in breast cancer 1 (
Rinske Drost, Kiranjit K. Dhillon, Hanneke van der Gulden, Ingrid van der Heijden, Inger Brandsma, Cristina Cruz, Dafni Chondronasiou, Marta Castroviejo-Bermejo, Ute Boon, Eva Schut, Eline van der Burg, Ellen Wientjens, Mark Pieterse, Christiaan Klijn, Sjoerd Klarenbeek, Fabricio Loayza-Puch, Ran Elkon, Liesbeth van Deemter, Sven Rottenberg, Marieke van de Ven, Dick H.W. Dekkers, Jeroen A.A. Demmers, Dik C. van Gent, Reuven Agami, Judith Balmaña, Violeta Serra, Toshiyasu Taniguchi, Peter Bouwman, Jos Jonkers
A rare subset of HIV-1–infected individuals is able to maintain plasma viral load (VL) at low levels without antiretroviral treatment. Identifying the mechanisms underlying this atypical response to infection may lead to therapeutic advances for treating HIV-1. Here, we developed a proteomic analysis to compare peripheral blood cell proteomes in 20 HIV-1–infected individuals who maintained either high or low VL with the aim of identifying host factors that impact HIV-1 replication. We determined that the levels of multiple histone proteins were markedly decreased in cohorts of individuals with high VL. This reduction was correlated with lower levels of stem-loop binding protein (SLBP), which is known to control histone metabolism. Depletion of cellular SLBP increased promoter engagement with the chromatin structures of the host gene high mobility group protein A1 (
Ming Li, Lynne D. Tucker, John M. Asara, Collins K. Cheruiyot, Huafei Lu, Zhijin J. Wu, Michael C. Newstein, Mark S. Dooner, Jennifer Friedman, Michelle A. Lally, Bharat Ramratnam
Following immune attack, solid tumors upregulate coinhibitory ligands that bind to inhibitory receptors on T cells. This adaptive resistance compromises the efficacy of chimeric antigen receptor (CAR) T cell therapies, which redirect T cells to solid tumors. Here, we investigated whether programmed death-1–mediated (PD-1–mediated) T cell exhaustion affects mesothelin-targeted CAR T cells and explored cell-intrinsic strategies to overcome inhibition of CAR T cells. Using an orthotopic mouse model of pleural mesothelioma, we determined that relatively high doses of both CD28- and 4-1BB–based second-generation CAR T cells achieved tumor eradication. CAR-mediated CD28 and 4-1BB costimulation resulted in similar levels of T cell persistence in animals treated with low T cell doses; however, PD-1 upregulation within the tumor microenvironment inhibited T cell function. At lower doses, 4-1BB CAR T cells retained their cytotoxic and cytokine secretion functions longer than CD28 CAR T cells. The prolonged function of 4-1BB CAR T cells correlated with improved survival. PD-1/PD-1 ligand [PD-L1] pathway interference, through PD-1 antibody checkpoint blockade, cell-intrinsic PD-1 shRNA blockade, or a PD-1 dominant negative receptor, restored the effector function of CD28 CAR T cells. These findings provide mechanistic insights into human CAR T cell exhaustion in solid tumors and suggest that PD-1/PD-L1 blockade may be an effective strategy for improving the potency of CAR T cell therapies.
Leonid Cherkassky, Aurore Morello, Jonathan Villena-Vargas, Yang Feng, Dimiter S. Dimitrov, David R. Jones, Michel Sadelain, Prasad S. Adusumilli
Uncontrolled inflammation underpins a diverse range of diseases where effective therapy remains an unmet clinical need. Hypoxia is a prominent feature of the inflammatory microenvironment that regulates key transcription factors including HIF and NF-κB in both innate and adaptive immune cells. In turn, altered activity of the pathways controlled by these factors can affect the course of inflammation through the regulation of immune cell development and function. In this review, we will discuss these pathways and the oxygen sensors that confer hypoxic sensitivity in immune cells. Furthermore, we will describe how hypoxia-dependent pathways contribute to immunity and discuss their potential as therapeutic targets in inflammatory and infectious disease.
Cormac T. Taylor, Glen Doherty, Padraic G. Fallon, Eoin P. Cummins
E2F-mediated transcriptional repression of cell cycle–dependent gene expression is critical for the control of cellular proliferation, survival, and development. E2F signaling also interacts with transcriptional programs that are downstream of genetic predictors for cancer development, including hepatocellular carcinoma (HCC). Here, we evaluated the function of the atypical repressor genes
Lindsey N. Kent, Jessica B. Rakijas, Shusil K. Pandit, Bart Westendorp, Hui-Zi Chen, Justin T. Huntington, Xing Tang, Sooin Bae, Arunima Srivastava, Shantibhusan Senapati, Christopher Koivisto, Chelsea K. Martin, Maria C. Cuitino, Miguel Perez, Julian M. Clouse, Veda Chokshi, Neelam Shinde, Raleigh Kladney, Daokun Sun, Antonio Perez-Castro, Ramadhan B. Matondo, Sathidpak Nantasanti, Michal Mokry, Kun Huang, Raghu Machiraju, Soledad Fernandez, Thomas J. Rosol, Vincenzo Coppola, Kamal S. Pohar, James M. Pipas, Carl R. Schmidt, Alain de Bruin, Gustavo Leone
Tumor suppression that is mediated by oncogene-induced senescence (OIS) is considered to function as a safeguard during development of pancreatic ductal adenocarcinoma (PDAC). However, the mechanisms that regulate OIS in PDAC are poorly understood. Here, we have determined that nuclear RelA reinforces OIS to inhibit carcinogenesis in the
Marina Lesina, Sonja Maria Wörmann, Jennifer Morton, Kalliope Nina Diakopoulos, Olga Korneeva, Margit Wimmer, Henrik Einwächter, Jan Sperveslage, Ihsan Ekin Demir, Timo Kehl, Dieter Saur, Bence Sipos, Mathias Heikenwälder, Jörg Manfred Steiner, Timothy Cragin Wang, Owen J. Sansom, Roland Michael Schmid, Hana Algül
Eleftheria Lefkou, Apostolos Mamopoulos, Themistoklis Dagklis, Christos Vosnakis, David Rousso, Guillermina Girardi
Patients with cancers that harbor breast cancer 1 (
Yifan Wang, John J. Krais, Andrea J. Bernhardy, Emmanuelle Nicolas, Kathy Q. Cai, Maria I. Harrell, Hyoung H. Kim, Erin George, Elizabeth M. Swisher, Fiona Simpkins, Neil Johnson
Inflammation and oxidative stress are known risk factors for preterm birth (PTB); however, the mechanisms and pathways that influence this condition are not fully described. Previously, we showed that mTORC1 signaling is increased in mice harboring a uterine-specific deletion of transformation-related protein 53 (
Wenbo Deng, Jeeyeon Cha, Jia Yuan, Hirofumi Haraguchi, Amanda Bartos, Emma Leishman, Benoit Viollet, Heather B. Bradshaw, Yasushi Hirota, Sudhansu K. Dey
The recent clinical success of chimeric antigen receptor (CAR) T cell therapy for B cell malignancies represents a paradigm shift in cancer immunotherapy. Unfortunately, application of CAR T cell–mediated therapy for solid tumors has so far been disappointing, and the reasons for this poor response in solid tumors remain unknown. In this issue of the
Xiaopei Huang, Yiping Yang
Pregnant women with antiphospholipid syndrome (APS) are at a high risk of obstetrical complications. The current standard of care, including the use of low-dose aspirin and heparin, has not been shown to prevent preeclampsia or intrauterine growth restriction (IUGR). Due to the similarities in pathophysiology among preeclampsia, IUGR, and atherosclerotic cardiovascular disease, statins have been proposed for treating and/or preventing these obstetrical complications. In this issue of the
Maged M. Costantine
Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer in which NF-κB pathways promote biological aggressiveness. In this issue of the
Germline breast cancer 1 (
Simon N. Powell
Lin Ding, Michael M. Hayes, Amanda Photenhauer, Kathryn A. Eaton, Qian Li, Ramon Ocadiz-Ruiz, Juanita L. Merchant
The structural maintenance of chromosomes (SMC) family of proteins supports mitotic proliferation, meiosis, and DNA repair to control genomic stability. Impairments in chromosome maintenance are linked to rare chromosome breakage disorders. Here, we have identified a chromosome breakage syndrome associated with severe lung disease in early childhood. Four children from two unrelated kindreds died of severe pulmonary disease during infancy following viral pneumonia with evidence of combined T and B cell immunodeficiency. Whole exome sequencing revealed biallelic missense mutations in the
Saskia N. van der Crabben, Marije P. Hennus, Grant A. McGregor, Deborah I. Ritter, Sandesh C.S. Nagamani, Owen S. Wells, Magdalena Harakalova, Ivan K. Chinn, Aaron Alt, Lucie Vondrova, Ron Hochstenbach, Joris M. van Montfrans, Suzanne W. Terheggen-Lagro, Stef van Lieshout, Markus J. van Roosmalen, Ivo Renkens, Karen Duran, Isaac J. Nijman, Wigard P. Kloosterman, Eric Hennekam, Jordan S. Orange, Peter M. van Hasselt, David A. Wheeler, Jan J. Palecek, Alan R. Lehmann, Antony W. Oliver, Laurence H. Pearl, Sharon E. Plon, Johanne M. Murray, Gijs van Haaften
M1 and M2 macrophage phenotypes, which mediate proinflammatory and antiinflammatory functions, respectively, represent the extremes of immunoregulatory plasticity in the macrophage population. This plasticity can also result in intermediate macrophage states that support a balance between these opposing functions. In sepsis, M1 macrophages can compensate for hyperinflammation by acquiring an M2-like immunosuppressed status that increases the risk of secondary infection and death. The M1 to M2 macrophage reprogramming that develops during LPS tolerance resembles the pathological antiinflammatory response to sepsis. Here, we determined that p21 regulates macrophage reprogramming by shifting the balance between active p65-p50 and inhibitory p50-p50 NF-κB pathways. p21 deficiency reduced the DNA-binding affinity of the p50-p50 homodimer in LPS-primed and -rechallenged macrophages, impairing their ability to attenuate IFN-β production and acquire an M2-like hyporesponsive status. High p21 levels in sepsis patients correlated with low IFN-β expression, and p21 knockdown in human monocytes corroborated its role in IFN-β regulation. The data demonstrate that p21 adjusts the equilibrium between p65-p50 and p50-p50 NF-κB pathways to mediate macrophage plasticity in LPS tolerance. Identifying p21-related pathways involved in monocyte reprogramming may lead to potential targets for sepsis treatment.
Gorjana Rackov, Enrique Hernández-Jiménez, Rahman Shokri, Lorena Carmona-Rodríguez, Santos Mañes, Melchor Álvarez-Mon, Eduardo López-Collazo, Carlos Martínez-A, Dimitrios Balomenos
In preclinical models of glioblastoma, antigen escape variants can lead to tumor recurrence after treatment with CAR T cells that are redirected to single tumor antigens. Given the heterogeneous expression of antigens on glioblastomas, we hypothesized that a bispecific CAR molecule would mitigate antigen escape and improve the antitumor activity of T cells. Here, we created a CAR that joins a HER2-binding scFv and an IL13Rα2-binding IL-13 mutein to make a tandem CAR exodomain (TanCAR) and a CD28.ζ endodomain. We determined that patient TanCAR T cells showed distinct binding to HER2 or IL13Rα2 and had the capability to lyse autologous glioblastoma. TanCAR T cells exhibited activation dynamics that were comparable to those of single CAR T cells upon encounter of HER2 or IL13Rα2. We observed that TanCARs engaged HER2 and IL13Rα2 simultaneously by inducing HER2-IL13Rα2 heterodimers, which promoted superadditive T cell activation when both antigens were encountered concurrently. TanCAR T cell activity was more sustained but not more exhaustible than that of T cells that coexpressed a HER2 CAR and an IL13Rα2 CAR, T cells with a unispecific CAR, or a pooled product. In a murine glioblastoma model, TanCAR T cells mitigated antigen escape, displayed enhanced antitumor efficacy, and improved animal survival. Thus, TanCAR T cells show therapeutic potential to improve glioblastoma control by coengaging HER2 and IL13Rα2 in an augmented, bivalent immune synapse that enhances T cell functionality and reduces antigen escape.
Meenakshi Hegde, Malini Mukherjee, Zakaria Grada, Antonella Pignata, Daniel Landi, Shoba A. Navai, Amanda Wakefield, Kristen Fousek, Kevin Bielamowicz, Kevin K.H. Chow, Vita S. Brawley, Tiara T. Byrd, Simone Krebs, Stephen Gottschalk, Winfried S. Wels, Matthew L. Baker, Gianpietro Dotti, Maksim Mamonkin, Malcolm K. Brenner, Jordan S. Orange, Nabil Ahmed
Joints that have degenerated as a result of aging or injury contain dead chondrocytes and damaged cartilage. Some studies have suggested that chondrocyte death precedes cartilage damage, but how the loss of chondrocytes affects cartilage integrity is not clear. In this study, we examined whether chondrocyte death undermines cartilage integrity in aging and injury using a rapid 3D confocal cartilage imaging technique coupled with standard histology. We induced autonomous expression of diphtheria toxin to kill articular surface chondrocytes in mice and determined that chondrocyte death did not lead to cartilage damage. Moreover, cartilage damage after surgical destabilization of the medial meniscus of the knee was increased in mice with intact chondrocytes compared with animals whose chondrocytes had been killed, suggesting that chondrocyte death does not drive cartilage damage in response to injury. These data imply that chondrocyte catabolism, not death, contributes to articular cartilage damage following injury. Therefore, therapies targeted at reducing the catabolic phenotype may protect against degenerative joint disease.
Minjie Zhang, Sriniwasan B. Mani, Yao He, Amber M. Hall, Lin Xu, Yefu Li, David Zurakowski, Gregory D. Jay, Matthew L. Warman
Vision impairments and blindness caused by retinitis pigmentosa result from severe neurodegeneration that leads to a loss of photoreceptors, the specialized light-sensitive neurons that enable vision. Although the mammalian nervous system is unable to replace neurons lost due to degeneration, therapeutic approaches to reprogram resident glial cells to replace retinal neurons have been proposed. Here, we demonstrate that retinal Müller glia can be reprogrammed in vivo into retinal precursors that then differentiate into photoreceptors. We transplanted hematopoietic stem and progenitor cells (HSPCs) into retinas affected by photoreceptor degeneration and observed spontaneous cell fusion events between Müller glia and the transplanted cells. Activation of Wnt signaling in the transplanted HSPCs enhanced survival and proliferation of Müller-HSPC hybrids as well as their reprogramming into intermediate photoreceptor precursors. This suggests that Wnt signaling drives the reprogrammed cells toward a photoreceptor progenitor fate. Finally, Müller-HSPC hybrids differentiated into photoreceptors. Transplantation of HSPCs with activated Wnt functionally rescued the retinal degeneration phenotype in
Daniela Sanges, Giacoma Simonte, Umberto Di Vicino, Neus Romo, Isabel Pinilla, Marta Nicolás Farrés, Maria Pia Cosma
Risk for ischemic stroke has a strong genetic basis, but heritable factors also contribute to the extent of damage after a stroke has occurred. We previously identified a locus on distal mouse chromosome 7 that contributes over 50% of the variation in postischemic cerebral infarct volume observed between inbred strains. Here, we used ancestral haplotype analysis to fine-map this locus to 12 candidate genes. The gene encoding the IL-21 receptor (
Han Kyu Lee, Sehoon Keum, Huaxin Sheng, David S. Warner, Donald C. Lo, Douglas A. Marchuk
Diabetic retinopathy (DR) is a major complication of diabetes and a leading cause of blindness in the working-age population. Impaired blood-retinal barrier function leads to macular edema that is closely associated with the deterioration of central vision. We previously demonstrated that the neuronal guidance cue netrin-1 activates a program of reparative angiogenesis in microglia within the ischemic retina. Here, we provide evidence in both vitreous humor of diabetic patients and in retina of a murine model of diabetes that netrin-1 is metabolized into a bioactive fragment corresponding to domains VI and V of the full-length molecule. In contrast to the protective effects of full-length netrin-1 on retinal microvasculature, the VI-V fragment promoted vascular permeability through the uncoordinated 5B (UNC5B) receptor. The collagenase matrix metalloprotease 9 (MMP-9), which is increased in patients with diabetic macular edema, was capable of cleaving netrin-1 into the VI-V fragment. Thus, MMP-9 may release netrin-1 fragments from the extracellular matrix and facilitate diffusion. Nonspecific inhibition of collagenases or selective inhibition of MMP-9 decreased pathological vascular permeability in a murine model of diabetic retinal edema. This study reveals that netrin-1 degradation products are capable of modulating vascular permeability, suggesting that these fragments are of potential therapeutic interest for the treatment of DR.
Khalil Miloudi, François Binet, Ariel Wilson, Agustin Cerani, Malika Oubaha, Catherine Menard, Sullivan Henriques, Gaelle Mawambo, Agnieszka Dejda, Phuong Trang Nguyen, Flavio A. Rezende, Steve Bourgault, Timothy E. Kennedy, Przemyslaw Sapieha
Progressive tissue fibrosis is a major cause of the morbidity and mortality associated with repeated epithelial injuries and accumulation of myofibroblasts. Successful treatment options are limited by an incomplete understanding of the molecular mechanisms that regulate myofibroblast accumulation. Here, we employed in vivo lineage tracing and real-time gene expression transgenic reporting methods to analyze the early embryonic transcription factor T-box gene 4 (TBX4), and determined that TBX4-lineage mesenchymal progenitors are the predominant source of myofibroblasts in injured adult lung. In a murine model, ablation of TBX4-expressing cells or disruption of TBX4 signaling attenuated lung fibrosis after bleomycin-induced injury. Furthermore, TBX4 regulated hyaluronan synthase 2 production to enable fibroblast invasion of matrix both in murine models and in fibroblasts from patients with severe pulmonary fibrosis. These data identify TBX4 as a mesenchymal transcription factor that drives accumulation of myofibroblasts and the development of lung fibrosis. Targeting TBX4 and downstream factors that regulate fibroblast invasiveness could lead to therapeutic approaches in lung fibrosis.
Ting Xie, Jiurong Liang, Ningshan Liu, Caijuan Huan, Yanli Zhang, Weijia Liu, Maya Kumar, Rui Xiao, Jeanine D’Armiento, Daniel Metzger, Pierre Chambon, Virginia E. Papaioannou, Barry R. Stripp, Dianhua Jiang, Paul W. Noble
Hydrops fetalis describes fluid accumulation in at least 2 fetal compartments, including abdominal cavities, pleura, and pericardium, or in body tissue. The majority of hydrops fetalis cases are nonimmune conditions that present with generalized edema of the fetus, and approximately 15% of these nonimmune cases result from a lymphatic abnormality. Here, we have identified an autosomal dominant, inherited form of lymphatic-related (nonimmune) hydrops fetalis (LRHF). Independent exome sequencing projects on 2 families with a history of in utero and neonatal deaths associated with nonimmune hydrops fetalis uncovered 2 heterozygous missense variants in the gene encoding Eph receptor B4 (
Silvia Martin-Almedina, Ines Martinez-Corral, Rita Holdhus, Andres Vicente, Elisavet Fotiou, Shin Lin, Kjell Petersen, Michael A. Simpson, Alexander Hoischen, Christian Gilissen, Heather Jeffery, Giles Atton, Christina Karapouliou, Glen Brice, Kristiana Gordon, John W. Wiseman, Marianne Wedin, Stanley G. Rockson, Steve Jeffery, Peter S. Mortimer, Michael P. Snyder, Siren Berland, Sahar Mansour, Taija Makinen, Pia Ostergaard
The chronic inflammatory state that accompanies obesity is a major contributor to insulin resistance and other dysfunctional adaptations in adipose tissue. Cellular and secreted factors promote the inflammatory milieu of obesity, but the transcriptional pathways that drive these processes are not well described. Although the canonical inflammatory transcription factor NF-κB is considered to be the major driver of adipocyte inflammation, members of the interferon regulatory factor (IRF) family may also play a role in this process. Here, we determined that IRF3 expression is upregulated in the adipocytes of obese mice and humans. Signaling through TLR3 and TLR4, which lie upstream of IRF3, induced insulin resistance in murine adipocytes, while IRF3 knockdown prevented insulin resistance. Furthermore, improved insulin sensitivity in IRF3-deficient mice was associated with reductions in intra-adipose and systemic inflammation in the high fat–fed state, enhanced browning of subcutaneous fat, and increased adipose expression of GLUT4. Taken together, the data indicate that IRF3 is a major transcriptional regulator of adipose inflammation and is involved in maintaining systemic glucose and energy homeostasis.
Manju Kumari, Xun Wang, Louise Lantier, Anna Lyubetskaya, Jun Eguchi, Sona Kang, Danielle Tenen, Hyun Cheol Roh, Xingxing Kong, Lawrence Kazak, Rasheed Ahmad, Evan D. Rosen
Hypertriglyceridemia is an independent risk factor for cardiovascular disease, and plasma triglycerides (TGs) correlate strongly with plasma apolipoprotein C-III (ApoC-III) levels. Antisense oligonucleotides (ASOs) for ApoC-III reduce plasma TGs in primates and mice, but the underlying mechanism of action remains controversial. We determined that a murine-specific ApoC-III–targeting ASO reduces fasting TG levels through a mechanism that is dependent on low-density lipoprotein receptors (LDLRs) and LDLR-related protein 1 (LRP1). ApoC-III ASO treatment lowered plasma TGs in mice lacking lipoprotein lipase (LPL), hepatic heparan sulfate proteoglycan (HSPG) receptors, LDLR, or LRP1 and in animals with combined deletion of the genes encoding HSPG receptors and LDLRs or LRP1. However, the ApoC-III ASO did not lower TG levels in mice lacking both LDLR and LRP1. LDLR and LRP1 were also required for ApoC-III ASO–induced reduction of plasma TGs in mice fed a high-fat diet, in postprandial clearance studies, and when ApoC-III–rich or ApoC-III–depleted lipoproteins were injected into mice. ASO reduction of ApoC-III had no effect on VLDL secretion, heparin-induced TG reduction, or uptake of lipids into heart and skeletal muscle. Our data indicate that ApoC-III inhibits turnover of TG-rich lipoproteins primarily through a hepatic clearance mechanism mediated by the LDLR/LRP1 axis.
Philip L.S.M. Gordts, Ryan Nock, Ni-Huiping Son, Bastian Ramms, Irene Lew, Jon C. Gonzales, Bryan E. Thacker, Debapriya Basu, Richard G. Lee, Adam E. Mullick, Mark J. Graham, Ira J. Goldberg, Rosanne M. Crooke, Joseph L. Witztum, Jeffrey D. Esko
Hypertrophic cardiomyopathy is a common cause of mortality in congenital heart disease (CHD). Many gene abnormalities are associated with cardiac hypertrophy, but their function in cardiac development is not well understood. Loss-of-function mutations in
Jessica Lauriol, Janel R. Cabrera, Ashbeel Roy, Kimberly Keith, Sara M. Hough, Federico Damilano, Bonnie Wang, Gabriel C. Segarra, Meaghan E. Flessa, Lauren E. Miller, Saumya Das, Roderick Bronson, Kyu-Ho Lee, Maria I. Kontaridis
The immune response against transplanted allografts is one of the most potent reactions mounted by the immune system. The acute rejection response has been attributed to donor dendritic cells (DCs), which migrate to recipient lymphoid tissues and directly activate alloreactive T cells against donor MHC molecules. Here, using a murine heart transplant model, we determined that only a small number of donor DCs reach lymphoid tissues and investigated how this limited population of donor DCs efficiently initiates the alloreactive T cell response that causes acute rejection. In our mouse model, efficient passage of donor MHC molecules to recipient conventional DCs (cDCs) was dependent on the transfer of extracellular vesicles (EVs) from donor DCs that migrated from the graft to lymphoid tissues. These EVs shared characteristics with exosomes and were internalized or remained attached to the recipient cDCs. Recipient cDCs that acquired exosomes became activated and triggered full activation of alloreactive T cells. Depletion of recipient cDCs after cardiac transplantation drastically decreased presentation of donor MHC molecules to directly alloreactive T cells and delayed graft rejection in mice. These findings support a key role for transfer of donor EVs in the generation of allograft-targeting immune responses and suggest that interrupting this process has potential to dampen the immune response to allografts.
Quan Liu, Darling M. Rojas-Canales, Sherrie J. Divito, William J. Shufesky, Donna Beer Stolz, Geza Erdos, Mara L.G. Sullivan, Gregory A. Gibson, Simon C. Watkins, Adriana T. Larregina, Adrian E. Morelli
Federico Iovino, Disa L. Hammarlöf, Genevieve Garriss, Sarah Brovall, Priyanka Nannapaneni, Birgitta Henriques-Normark
Mutations in the T-box transcription factor TBX20 are associated with multiple forms of congenital heart defects, including cardiac septal abnormalities, but our understanding of the contributions of endocardial TBX20 to heart development remains incomplete. Here, we investigated how TBX20 interacts with endocardial gene networks to drive the mesenchymal and myocardial movements that are essential for outflow tract and atrioventricular septation. Selective ablation of
Cornelis J. Boogerd, Ivy Aneas, Noboru Sakabe, Ralph J. Dirschinger, Quen J. Cheng, Bin Zhou, Ju Chen, Marcelo A. Nobrega, Sylvia M. Evans
Aggregation of α-synuclein contributes to the formation of Lewy bodies and neurites, the pathologic hallmarks of Parkinson disease (PD) and α-synucleinopathies. Although a number of human mutations have been identified in familial PD, the mechanisms that promote α-synuclein accumulation and toxicity are poorly understood. Here, we report that hyperactivity of the nonreceptor tyrosine kinase c-Abl critically regulates α-synuclein–induced neuropathology. In mice expressing a human α-synucleinopathy–associated mutation (hA53Tα-syn mice), deletion of the gene encoding c-Abl reduced α-synuclein aggregation, neuropathology, and neurobehavioral deficits. Conversely, overexpression of constitutively active c-Abl in hA53Tα-syn mice accelerated α-synuclein aggregation, neuropathology, and neurobehavioral deficits. Moreover, c-Abl activation led to an age-dependent increase in phosphotyrosine 39 α-synuclein. In human postmortem samples, there was an accumulation of phosphotyrosine 39 α-synuclein in brain tissues and Lewy bodies of PD patients compared with age-matched controls. Furthermore, in vitro studies show that c-Abl phosphorylation of α-synuclein at tyrosine 39 enhances α-synuclein aggregation. Taken together, this work establishes a critical role for c-Abl in α-synuclein–induced neurodegeneration and demonstrates that selective inhibition of c-Abl may be neuroprotective. This study further indicates that phosphotyrosine 39 α-synuclein is a potential disease indicator for PD and related α-synucleinopathies.
Saurav Brahmachari, Preston Ge, Su Hyun Lee, Donghoon Kim, Senthilkumar S. Karuppagounder, Manoj Kumar, Xiaobo Mao, Joo Ho Shin, Yunjong Lee, Olga Pletnikova, Juan C. Troncoso, Valina L. Dawson, Ted M. Dawson, Han Seok Ko
Pain is a life-long symptom in sickle cell disease (SCD) and a predictor of disease progression and mortality, but little is known about its molecular mechanisms. Here, we characterized pain in a targeted knockin mouse model of SCD (TOW mouse) that exclusively expresses human alleles encoding normal α- and sickle β-globin. TOW mice exhibited ongoing spontaneous pain behavior and increased sensitivity to evoked pain compared with littermate control mice expressing normal human hemoglobins. PKCδ activation was elevated in the superficial laminae of the spinal cord dorsal horn in TOW mice, specifically in GABAergic inhibitory neurons. Functional inhibition and neuron-specific silencing of PKCδ attenuated spontaneous pain, mechanical allodynia, and heat hyperalgesia in TOW mice. Furthermore, we took a hematopoietic stem cell transplantation approach to generating a SCD model in PKCδ-deficient mice. Neither spontaneous pain nor evoked pain was detected in the mice lacking PKCδ despite full establishment of SCD phenotypes. These findings support a critical role of spinal PKCδ in the development of chronic pain in SCD, which may become a potential target for pharmacological interventions.
Ying He, Diana J. Wilkie, Jonathan Nazari, Rui Wang, Robert O. Messing, Joseph DeSimone, Robert E. Molokie, Zaijie Jim Wang
Inflammatory myofibroblastic tumors (IMTs) are characterized by myofibroblast proliferation and an inflammatory cell infiltrate. Little is known about the molecular pathways that precipitate IMT formation. Here, we report the identification of somatic mutations in
JingWei Lu, Terra-Dawn Plank, Fang Su, XiuJuan Shi, Chen Liu, Yuan Ji, ShuaiJun Li, Andrew Huynh, Chao Shi, Bo Zhu, Guang Yang, YanMing Wu, Miles F. Wilkinson, YanJun Lu