Abstract:
:Hearing relies on mechanically gated ion channels present in the actin-rich stereocilia bundles at the apical surface of cochlear hair cells. Our knowledge of the mechanisms underlying the formation and maintenance of the sound-receptive structure is limited. Utilizing a large-scale forward genetic screen in mice, genome mapping and gene complementation tests, we identified Clrn2 as a new deafness gene. The Clrn2clarinet/clarinet mice (p.Trp4* mutation) exhibit a progressive, early-onset hearing loss, with no overt retinal deficits. Utilizing data from the UK Biobank study, we could show that CLRN2 is involved in human non-syndromic progressive hearing loss. Our in-depth morphological, molecular and functional investigations establish that while it is not required for initial formation of cochlear sensory hair cell stereocilia bundles, clarin-2 is critical for maintaining normal bundle integrity and functioning. In the differentiating hair bundles, lack of clarin-2 leads to loss of mechano-electrical transduction, followed by selective progressive loss of the transducing stereocilia. Together, our findings demonstrate a key role for clarin-2 in mammalian hearing, providing insights into the interplay between mechano-electrical transduction and stereocilia maintenance.
journal_name
EMBO Mol Medjournal_title
EMBO molecular medicineauthors
Dunbar LA,Patni P,Aguilar C,Mburu P,Corns L,Wells HR,Delmaghani S,Parker A,Johnson S,Williams D,Esapa CT,Simon MM,Chessum L,Newton S,Dorning J,Jeyarajan P,Morse S,Lelli A,Codner GF,Peineau T,Gopal SR,Alagramam Kdoi
10.15252/emmm.201910288subject
Has Abstractpub_date
2019-09-01 00:00:00pages
e10288issue
9eissn
1757-4676issn
1757-4684journal_volume
11pub_type
杂志文章abstract::We survive because we adapted to a world of microorganisms. All our epithelial surfaces participate in keeping up an effective barrier against microbes while not initiating ongoing inflammatory processes and risking collateral damage to the host. Major players in this scenario are antimicrobial peptides (AMPs). Such b...
journal_title:EMBO molecular medicine
pub_type: 杂志文章,评审
doi:10.1002/emmm.201201773
更新日期:2013-10-01 00:00:00
abstract::Disease modeling with induced pluripotent stem cells (iPSCs) is creating an abundance of phenotypic information that has become difficult to follow and interpret. Here, we report a systematic analysis of research practices and reporting bias in neurological disease models from 93 published articles. We find heterogene...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201708191
更新日期:2017-12-01 00:00:00
abstract::Highly active antiretroviral therapy (HAART) has improved the outlook for the HIV epidemic, but does not provide a cure. The proposed "shock-and-kill" strategy is directed at inducing latent HIV reservoirs, which may then be purged via boosted immune response or targeting infected cells. We describe five novel compoun...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201708193
更新日期:2018-02-01 00:00:00
abstract::The angiopoietin (Ang)-Tie pathway has been intensely pursued as candidate second-generation anti-angiogenic target. While much of the translational work has focused on the ligand Ang2, the clinical efficacy of Ang2-targeting drugs is limited and failed to improve patient survival. In turn, the orphan receptor Tie1 re...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201911164
更新日期:2020-06-08 00:00:00
abstract::Immunotherapeutic approaches are currently the most advanced treatments for Alzheimer's disease (AD). Antibodies against amyloid β-peptide (Aβ) bind to amyloid plaques and induce their clearance by microglia via Fc receptor-mediated phagocytosis. Dysfunctions of microglia may play a pivotal role in AD pathogenesis and...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201606370
更新日期:2016-09-01 00:00:00
abstract::The tumor suppressor gene TP53 is the most frequently mutated gene in cancer. The compound APR-246 (PRIMA-1Met/Eprenetapopt) is converted to methylene quinuclidinone (MQ) that targets mutant p53 protein and perturbs cellular antioxidant balance. APR-246 is currently tested in a phase III clinical trial in myelodysplas...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201910852
更新日期:2020-12-14 00:00:00
abstract::KCNN3, encoding the small conductance calcium-activated potassium channel SK3, harbours a polymorphic CAG repeat in the amino-terminal coding region with yet unproven function. Hypothesizing that KCNN3 genotypes do not influence susceptibility to schizophrenia but modify its phenotype, we explored their contribution t...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.1002/emmm.201100135
更新日期:2011-06-01 00:00:00
abstract::Conventional maximum-tolerated dose (MTD) chemotherapy relies on periodic, massive cancer cell ablation events followed by treatment-free intermissions, stereotypically resulting in resistance, relapse, and mortality. Furthermore, MTD chemotherapy can promote metastatic dissemination via activation of a transcriptiona...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201911416
更新日期:2020-09-07 00:00:00
abstract::Baricitinib is an oral Janus kinase (JAK)1/JAK2 inhibitor approved for the treatment of rheumatoid arthritis (RA) that was independently predicted, using artificial intelligence (AI) algorithms, to be useful for COVID-19 infection via proposed anti-cytokine effects and as an inhibitor of host cell viral propagation. W...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.202012697
更新日期:2020-08-07 00:00:00
abstract::In the normal quiescent vasculature, only 0.01% of endothelial cells (ECs) are proliferating. However, this proportion increases dramatically following the angiogenic switch during tumor growth or wound healing. Recent evidence suggests that this angiogenic switch is accompanied by a metabolic switch. Here, we show th...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.1002/emmm.201303016
更新日期:2014-05-01 00:00:00
abstract::Familial Mediterranean fever (FMF) is the most frequent hereditary systemic autoinflammatory syndrome. FMF is usually caused by biallelic mutations in the MEFV gene, encoding Pyrin. Conclusive genetic evidence lacks for about 30% of patients diagnosed with clinical FMF. Pyrin is an inflammasome sensor maintained inact...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201910547
更新日期:2019-11-07 00:00:00
abstract::High T-cell infiltration in colorectal cancer (CRC) correlates with a favorable disease outcome and immunotherapy response. This, however, is only observed in a small subset of CRC patients. A better understanding of the factors influencing tumor T-cell responses in CRC could inspire novel therapeutic approaches to ac...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201910681
更新日期:2020-01-09 00:00:00
abstract::Loss-of-function mutations in SMN1 cause spinal muscular atrophy (SMA), a leading genetic cause of infant mortality. The related SMN2 gene expresses suboptimal levels of functional SMN protein, due to a splicing defect. Many SMA patients reach adulthood, and there is also adult-onset (type IV) SMA. There is currently ...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.1002/emmm.201302567
更新日期:2013-10-01 00:00:00
abstract::Autologous haematopoietic stem cell transplantation is highly efficient for the treatment of systemic autoimmune diseases, but its consequences for the immune system remain poorly understood. Here, we describe an optimized RNA-based technology for unbiased amplification of T cell receptor beta-chain libraries and use ...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.1002/emmm.201100129
更新日期:2011-04-01 00:00:00
abstract::Dilated cardiomyopathy (DCM) is a life-threatening disorder whose genetic basis is heterogeneous and mostly unknown. Five Arab Christian infants, aged 4-30 months from four families, were diagnosed with DCM associated with mild skin, teeth, and hair abnormalities. All passed away before age 3. A homozygous sequence va...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201606523
更新日期:2017-03-01 00:00:00
abstract::Gene targeting constitutes a new step in the development of gene therapy for inherited diseases. Although previous studies have shown the feasibility of editing fibroblasts from Fanconi anemia (FA) patients, here we aimed at conducting therapeutic gene editing in clinically relevant cells, such as hematopoietic stem c...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201707540
更新日期:2017-11-01 00:00:00
abstract::In this report, we describe the development of a modified adeno-associated virus (AAV) capsid and promoter for transduction of retinal ON-bipolar cells. The bipolar cells, which are post-synaptic to the photoreceptors, are important retinal targets for both basic and preclinical research. In particular, a therapeutic ...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201404077
更新日期:2014-09-01 00:00:00
abstract::Focal epilepsy represents one of the most common chronic CNS diseases. The high incidence of drug resistance, devastating comorbidities, and insufficient responsiveness to surgery pose unmet medical challenges. In the quest of novel, disease-modifying treatment strategies of neuropeptides represent promising candidate...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201809963
更新日期:2019-10-01 00:00:00
abstract::Follistatin-like 1 (Fstl1) is a secreted protein that is acutely induced in heart following myocardial infarction (MI). In this study, we investigated cell type-specific regulation of Fstl1 and its function in a murine model of MI Fstl1 was robustly expressed in fibroblasts and myofibroblasts in the infarcted area com...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201506151
更新日期:2016-08-01 00:00:00
abstract::While increased VEGF-A has been associated with neovascular age-related macular degeneration (AMD), it is not known whether VEGF-A may also promote other age-related eye diseases. Here, we show that an increase in VEGF-A is sufficient to cause multiple distinct common aging diseases of the eye, including cataracts and...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201505613
更新日期:2016-03-01 00:00:00
abstract::Atherosclerosis, the major cause of cardiovascular disease, is a chronic inflammatory disease characterized by the accumulation of lipids and inflammatory cells in the artery wall. Aberrant expression of microRNAs has been implicated in the pathophysiological processes underlying the progression of atherosclerosis. He...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201607492
更新日期:2017-09-01 00:00:00
abstract::Disturbances in the morphology and function of mitochondria cause neurological diseases, which can affect the central and peripheral nervous system. The i-AAA protease YME1L ensures mitochondrial proteostasis and regulates mitochondrial dynamics by processing of the dynamin-like GTPase OPA1. Mutations in YME1L cause a...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201809288
更新日期:2019-01-01 00:00:00
abstract::Cannabis abuse during adolescence confers an increased risk for developing later in life cognitive deficits reminiscent of those observed in schizophrenia, suggesting common pathological mechanisms that remain poorly characterized. In line with previous findings that revealed a role of 5-HT6 receptor-operated mTOR act...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201910605
更新日期:2020-05-08 00:00:00
abstract::The current seasonal inactivated influenza vaccine protects only against a narrow range of virus strains as it triggers a dominant antibody response toward the hypervariable hemagglutinin (HA) head region. The discovery of rare broadly protective antibodies against conserved regions in influenza virus proteins has pro...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201910938
更新日期:2020-05-08 00:00:00
abstract::Various disorders including pseudoxanthoma elasticum (PXE) and generalized arterial calcification of infancy (GACI), which are caused by inactivating mutations in ABCC6 and ENPP1, respectively, present with extensive tissue calcification due to reduced plasma pyrophosphate (PPi). However, it has always been assumed th...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201707532
更新日期:2017-11-01 00:00:00
abstract::The cell fate determinant Numb is frequently downregulated in human breast cancers (BCs), resulting in p53 inactivation and an aggressive disease course. In the mouse mammary gland, Numb/p53 downregulation leads to aberrant tissue morphogenesis, expansion of the stem cell compartment, and emergence of cancer stem cell...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201606940
更新日期:2017-05-01 00:00:00
abstract::Clinical application of lentiviral vector (LV)-based hematopoietic stem and progenitor cells (HSPC) gene therapy is rapidly becoming a reality. Nevertheless, LV-mediated signaling and its potential functional consequences on HSPC biology remain poorly understood. We unravel here a remarkably limited impact of LV on th...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201707922
更新日期:2017-09-01 00:00:00
abstract::Phosphodiesterase type 10A (PDE10A) is highly enriched in striatum and is under evaluation as a drug target for several psychiatric/neurodegenerative diseases. Preclinical studies implicate PDE10A in the regulation of energy homeostasis, but the mechanisms remain unclear. By utilizing small-animal PET/MRI and the nove...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201506085
更新日期:2016-07-01 00:00:00
abstract::Metastatic castration-resistant prostate cancer (mCRPC) is a lethal form of treatment-resistant prostate cancer and poses significant therapeutic challenges. Deregulated receptor tyrosine kinase (RTK) signalling mediated by loss of tumour suppressor Sprouty2 (SPRY2) is associated with treatment resistance. Using pre-c...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201708347
更新日期:2018-04-01 00:00:00
abstract::Muscle-invasive forms of urothelial carcinomas are responsible for most mortality in bladder cancer. Finding new treatments for invasive bladder tumours requires adequate animal models to decipher the mechanisms of progression, in particular the way tumours interact with their microenvironment. Herein, using the murin...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.1002/emmm.201302655
更新日期:2013-12-01 00:00:00