Mechanisms of disease

  • Article
    | Open Access

    It is unclear how changes in gene expression are induced by changes in oxygen levels during late lung development. Here, the authors provide data from MULTI-seq scRNAseq in mice showing exposure to higher oxygen levels affects cell fates, especially for alveolarisation, and define gene/cell signatures of impaired lung development under hyperoxia.

    • Maria Hurskainen
    • , Ivana Mižíková
    •  & Bernard Thébaud
  • Article
    | Open Access

    TRPV4 dominant mutations cause neuropathy. Here, the authors show that TRPV4 binds and interacts with RhoA, modulating the actin cytoskeleton. Neuropathy-causing mutations of TRPV4 disrupt this complex, leading to RhoA activation and impairment of neurite extension in cultured cells and flies.

    • Brett A. McCray
    • , Erika Diehl
    •  & Charlotte J. Sumner
  • Article
    | Open Access

    Contacts between mitochondria and endoplasmatic reticulum (ER), and the transfer of calcium between them, have an important role in the regulation of cellular phenotypes, including senescence. Here the authors show that ITPR2 deficient mice display improved aging, associated with a decreased number of contacts between the mitochondria and the ER.

    • Dorian V. Ziegler
    • , David Vindrieux
    •  & David Bernard
  • Article
    | Open Access

    The mechanisms of how gain-of-function (GOF) mutant p53 drives carcinogenesis are unclear. Here, the authors show that a GOF mutant p53 requires its transactivation capability to induce mouse lung tumors and this is dependent on PLK3 phosphorylation of GOF mutant p53.

    • Catherine A. Vaughan
    • , Shilpa Singh
    •  & Sumitra Deb
  • Article
    | Open Access

    Animal models that fully recapitulate human CCM pathogenesis are not currently available. Here, the authors establish a novel CCM model and reveal that caveolae-Tie2 signaling is involved in CCMs formation at the level of venules, which is accompanied by gradual dissociation of pericytes.

    • Huanjiao Jenny Zhou
    • , Lingfeng Qin
    •  & Wang Min
  • Article
    | Open Access

    CTLA-4 is an important co-inhibitory receptor for T cells. Here, the authors show that CTLA-4 also has a function on B-1a cells, as conditional deletion results in activation of these cells and knockout mice develop an autoimmune profile.

    • Yang Yang
    • , Xiao Li
    •  & Leonore A. Herzenberg
  • Article
    | Open Access

    Muscle cells express an adhesion molecule called metavinculin, which has been associated with cardiomyopathies. Here, the authors employed molecular tension sensors to reveal that metavinculin expression modulates cell adhesion mechanics and they develop a mouse model to demonstrate that the presence of metavinculin is not as critical for heart muscle function as previously thought.

    • Verena Kanoldt
    • , Carleen Kluger
    •  & Carsten Grashoff
  • Article
    | Open Access

    Histone H3 at lysine 27 (H3K27M) is often mutated in cancer but its role in tumour initiation is unclear. Here, the authors generated a transgenic model expressing H3.3K27M from the Fabp7 gene promoter, demonstrating that H3.3K27M can initiate diverse tumorigesis on its own, acting through a RAS/MYC transcriptomic programme.

    • Sanja Pajovic
    • , Robert Siddaway
    •  & Cynthia Hawkins
  • Article
    | Open Access

    Cooperative interactions among tumor cells may have important implications for metastasis. Here, the authors examined the spatio-temporal nature of interactions among clonal populations of ovarian carcinoma cells and found that transient interactions cells can promote metastases via commensal interactions.

    • Suha Naffar-Abu Amara
    • , Hendrik J. Kuiken
    •  & Joan S. Brugge
  • Article
    | Open Access

    The cellular origins of lymphangioleiomyomatosis (LAM), a rare fatal lung disease, are poorly understood. Here the authors identify a mesenchymal cell hub coordinating the LAM phenotype and develop a LAM mouse model where they investigate the co-operative dysregulation of mTORC1 and WNT growth pathways in the sex- and age-specific changes leading to structural and functional decline.

    • Kseniya Obraztsova
    • , Maria C. Basil
    •  & Vera P. Krymskaya
  • Article
    | Open Access

    The human ICF 4 syndrome is caused by mutation of the chromatin remodeller LSH. Here, the authors show that LSH depletion disrupts the ability of histone variant macroH2A to insert into chromatin and silence transcription.

    • Kai Ni
    • , Jianke Ren
    •  & Kathrin Muegge
  • Article
    | Open Access

    Glaucoma is the leading cause of irreversible blindness affecting over 70 million people worldwide. Here, the authors show that inhibition of chronic ER stress-induced ATF4-CHOP-GADD34 signaling pathway rescues pathology in mouse models of glaucoma, thus suggesting a possible treatment strategy.

    • Ramesh B. Kasetti
    • , Pinkal D. Patel
    •  & Gulab S. Zode
  • Article
    | Open Access

    The (G4C2)-RNA hexanucleotide repeat expansion upstream of the start codon of the C9orf72 gene plays a critical role in familial ALS. The authors show that Sig1R, a ligand-regulated molecular chaperone, counteracts the aberrant nucleocytoplasmic distribution of Ran caused by the (G4C2)-RNA repeats.

    • Pin-Tse Lee
    • , Jean-Charles Liévens
    •  & Tsung-Ping Su
  • Article
    | Open Access

    Mutations in TREM2 alter risk for Alzheimer’s disease, though the mechanisms underlying risk in human cells are unclear. Here, the authors use iPS-microglia and chimeric mice to highlight altered survival, phagocytosis, migration, and transcriptional programs in microglia lacking TREM2.

    • Amanda McQuade
    • , You Jung Kang
    •  & Mathew Blurton-Jones
  • Article
    | Open Access

    Although acne vulgaris is the most common human inflammatory skin disease, its pathogenic mechanisms remain incompletely understood. Here the authors show that GATA6 is involved in maintaining homeostasis of the upper pilosebaceous unit of human skin and may contribute to acne pathogenesis.

    • Bénédicte Oulès
    • , Christina Philippeos
    •  & Fiona M. Watt
  • Article
    | Open Access

    ACE2 and TMPRSS2 have received recent attention as entry factors for SARS-CoV-2. Here the authors analyze nasal airway transcriptome data from 695 children determining ACE2 and TMPRSS2 expression is induced by viral and type2 inflammation, respectively, and both exhibit eQTLs that vary across world populations.

    • Satria P. Sajuthi
    • , Peter DeFord
    •  & Max A. Seibold
  • Article
    | Open Access

    Mutations in RAS-MAPK pathway genes are implicated in Noonan-spectrum, yet up to 20% of cases have unknown cause. Here, the authors identify RREB1 underlying a 6p microdeletion RASopathy-like syndrome and show that RREB1, SIN3A and KDM1A form a transcriptional repressive complex to control methylation of MAPK pathway genes.

    • Oliver A. Kent
    • , Manipa Saha
    •  & Robert Rottapel
  • Article
    | Open Access

    The failing heart is characterised by both alterations in mitochondrial metabolism and an elevation of cytosolic sodium. Here, the authors use 23Na NMR and metabolic profiling to show these are related, and that elevation in intracellular Na reprograms cardiac substrate utilisation via effects on mitochondrial Na/Ca exchange.

    • Dunja Aksentijević
    • , Anja Karlstaedt
    •  & Michael J. Shattock
  • Article
    | Open Access

    Cells employ different repair pathways to repair DNA double strand breaks. Here, the authors develop a CRISPR/Cas9-dependent method to study choices in DNA repair called the Color Assay Tracing-Repair (CAT-R) which simultaneously measure outcomes of DSB repair via end-protection and end-resection pathways.

    • Paris Roidos
    • , Stephanie Sungalee
    •  & Balca R. Mardin
  • Article
    | Open Access

    Abdominal adhesions are a common cause of bowel obstruction, but knowledge regarding adhesion biology and anti-adhesion therapies remains limited. Here the authors report a systematic analysis of mouse and human adhesion tissues demonstrating that visceral fibroblast JUN and associated PDGFRA expression promote adhesions, and JUN suppression can prevent adhesion formation.

    • Deshka S. Foster
    • , Clement D. Marshall
    •  & Michael T. Longaker
  • Article
    | Open Access

    Autosomal dominant optic atrophy is caused by mutations in the mitochondrial fusion protein OPA1. Here, the authors show that AMPK-induced autophagy depletes mitochondria in axons of retinal ganglion cells and that autophagic inhibition reverses vision loss in a mouse model.

    • Marta Zaninello
    • , Konstantinos Palikaras
    •  & Luca Scorrano
  • Article
    | Open Access

    Histones have a role in antimicrobial defense. Here, the authors show that the histone H2A and the antimicrobial peptide LL-37 exert synergistic effects by enhancing bacterial membrane pores and enabling H2A entry into the bacterial cytoplasm, where it reorganizes DNA and inhibits transcription.

    • Tory Doolin
    • , Henry M. Amir
    •  & Albert Siryaporn
  • Article
    | Open Access

    Severe head injury results in critical damage of blood vessels of the meninges and brain parenchyma. Here, the authors describe key pathways governing meningeal vascular regeneration following head injury, characterizing the differential roles of VEGFR2, Tie2, Dll4 and PDGFRβ signaling.

    • Bong Ihn Koh
    • , Hyuek Jong Lee
    •  & Injune Kim
  • Article
    | Open Access

    TLR4 signalling can reprogram the metabolism of macrophages to be more glycolytic and proinflammatory. Here the authors show that LPS and TLR4 signalling results in recruitment of TBK1, which in turn phosphorylates serine 727 on STAT3 to enable a proinflammatory switch via an effect on mitochondrial metabolism.

    • Jesse J. Balic
    • , Hassan Albargy
    •  & Ashley Mansell
  • Article
    | Open Access

    Familial carpal tunnel syndrome (CTS) is common, but causal genes are not characterized. Here the authors report two CTS-related mutations in two large families that impair secretion of COMP in tenocytes, leading to ER stress-induced unfolded protein response, inflammation and fibrosis in patients and mouse models.

    • Chunyu Li
    • , Ni Wang
    •  & Bo Gao
  • Article
    | Open Access

    Pathogenic bacteria of the genus Bartonella can induce vasoproliferative lesions during infection. Here, Tsukamoto et al. show that this effect is caused by a secreted protein that induces cell proliferation and angiogenesis by acting as an analog of the host’s vascular endothelial growth factor (VEGF).

    • Kentaro Tsukamoto
    • , Naoaki Shinzawa
    •  & Yohei Doi
  • Article
    | Open Access

    The molecular mechanisms regulating remyelination are unclear. Here, the authors show that promoting deacetylation of eEF1A1 prevents the translocation of Sox10 outside the nucleus, contributing to maintaining the expression of Sox10 target genes and increasing remyelination efficiency.

    • Mert Duman
    • , Adrien Vaquié
    •  & Claire Jacob
  • Article
    | Open Access

    The molecular mechanisms of acinar-to-ductal metaplasia (ADM) in the course of pancreatitis and cancer development are unclear. Here, the authors show that loss of κB-Ras and consequent Ral activation promotes tumour initiation and progression through persistent ADM and enhanced cell proliferation

    • Stephanie Beel
    • , Lina Kolloch
    •  & Andrea Oeckinghaus
  • Article
    | Open Access

    Defects in DNA single-strand break repair are associated with neurodegenerative disease. Here the authors reveal that mutations in ARH3 interfere with the catabolism of mono-(ADP-ribose) and lead to its accumulation on core histones following repair of endogenous or exogenous DNA single-strand breaks.

    • Hana Hanzlikova
    • , Evgeniia Prokhorova
    •  & Keith W. Caldecott
  • Article
    | Open Access

    Diamond Blackfan Anemia (DBA) is a congenital bone marrow failure syndrome that is associated with anemia. Here, the authors examine the role of Nemo-like kinase (NLK) in erythroid cells in the pathogenesis of DBA and as a potential target for therapy.

    • M. C. Wilkes
    • , K. Siva
    •  & K. M. Sakamoto
  • Article
    | Open Access

    The endolysosomal pathway plays an important role in regulating protein and lipid sorting and degradation. Here, the authors show that TMEM16K, an endoplasmic reticulum lipid scramblase, forms ER-endosome contact sites where it regulates endosomal sorting.

    • Maja Petkovic
    • , Juan Oses-Prieto
    •  & Yuh Nung Jan
  • Article
    | Open Access

    The majority of high grade serous ovarian cancers originate from fallopian tube secretory epithelial cells (FTSECs). Here the authors show that miR-181a drives oncogenic transformation in FTSECs through the cooperative inhibition of the tumor suppressor RB1 and of STING, resulting in genomic instability and suppression of intrinsic interferon signaling.

    • Matthew Knarr
    • , Rita A. Avelar
    •  & Analisa DiFeo
  • Article
    | Open Access

    Retinal vein occlusion can cause blindness, and features neuronal dysfunction, inflammation and breakdown of vascular integrity. Here the authors report a non-apoptotic role of endothelial caspase-9 in regulating blood-retina barrier integrity and neuronal survival, which can be therapeutically targeted in a mouse model of retinal vein occlusion.

    • Maria I. Avrutsky
    • , Crystal Colón Ortiz
    •  & Carol M. Troy
  • Article
    | Open Access

    Anorexia nervosa is an eating disorder characterized by fear of gaining weight that can lead to serious complications. Here the authors show that inhibition of SIRT1 is protective against the onset and progression of anorectic behavior in an activity-based anorexia model, suggesting SIRT1 could be a potential therapeutic target.

    • Timothy M. Robinette
    • , Justin W. Nicholatos
    •  & Sergiy Libert
  • Article
    | Open Access

    The DIS3L2 exonuclease degrades aberrant 7SL RNAs tagged by an oligouridine 3′-tail. Here the authors analyze DIS3L2 knockout mouse embryonic stem cells and suggest that DIS3L2-mediated quality control of 7SL RNA is important for ER-mediated translation and calcium ion homeostasis.

    • Mehdi Pirouz
    • , Chih-Hao Wang
    •  & Richard I. Gregory
  • Article
    | Open Access

    The relationship between histopathology, gene expression, and biochemical and mechanical properties of wounds is largely unknown. Here, the authors show that activin A alters wound healing at multiple levels by promoting pro-fibrotic gene expression and matrix deposition, thereby affecting biomechanical properties of skin wounds.

    • Mateusz S. Wietecha
    • , Marco Pensalfini
    •  & Sabine Werner