Featured
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Article
| Open AccessRRP7A links primary microcephaly to dysfunction of ribosome biogenesis, resorption of primary cilia, and neurogenesis
The RRP7A a gene is involved in ribosome biogenesis. Here the authors report a homozygous missense mutation segregating with primary microcephaly, and show that this occurs via functional defects in both nucleoli and primary cilia disrupting cell proliferation and neurogenesis.
- Muhammad Farooq
- , Louise Lindbæk
- & Lars Allan Larsen
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Article
| Open AccessmTORC1 activation in lung mesenchyme drives sex- and age-dependent pulmonary structure and function decline
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
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Article
| Open AccessThe circadian phase of antenatal glucocorticoid treatment affects the risk of behavioral disorders
Antenatal glucocorticoid therapy is indicated for mothers at risk of preterm delivery. Here, the authors show that the circadian phase of antenatal glucocorticoid treatment affects the risk of behavioral disorders later in life in mice and in a retrospective observational study in human infants.
- Mariana Astiz
- , Isabel Heyde
- & Henrik Oster
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Article
| Open AccessDissemination of RasV12-transformed cells requires the mechanosensitive channel Piezo
Drosophila tumours can be utilised to study the mechanisms of cell dissemination. Here, the authors use Drosophila midgut to examine the course of RasV12-transformed cell dissemination from midgut into circulation, which requires the actions of invasive protrusions and the mechanosensitive channel Piezo.
- Jiae Lee
- , Alejandra J. H. Cabrera
- & Young V. Kwon
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Article
| Open AccessLong-term alterations in brain and behavior after postnatal Zika virus infection in infant macaques
The consequences of postnatal Zika infection are not fully understood. Here, the authors show that postnatal Zika infection in infant rhesus macaques alters neurodevelopment resulting in social, cognitive and motor impairments, as well as structural and functional changes in the brain.
- Jessica Raper
- , Zsofia Kovacs-Balint
- & Ann Chahroudi
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Article
| Open AccessThe NMDA receptor regulates competition of epithelial cells in the Drosophila wing
Cell competition among epithelial cells allows removal of unfit or dangerous cells. Here, the authors show that the NMDA receptor is an important determinant of cell fitness in the Drosophila wing, also in the context of Myc super-competitor cells, with “loser” cells contributing metabolitic fuel to “winner” cells.
- Agnes R. Banreti
- & Pascal Meier
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Article
| Open AccessHuman and mouse essentiality screens as a resource for disease gene discovery
Discovery of causal variants for monogenic disorders has been facilitated by whole exome and genome sequencing, but does not provide a diagnosis for all patients. Here, the authors propose a Full Spectrum of Intolerance to Loss-of-Function (FUSIL) categorization that integrates gene essentiality information to aid disease gene discovery.
- Pilar Cacheiro
- , Violeta Muñoz-Fuentes
- & Coleen Kane
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Article
| Open AccessDstyk mutation leads to congenital scoliosis-like vertebral malformations in zebrafish via dysregulated mTORC1/TFEB pathway
Congenital scoliosis is a complex genetic disorder characterized by vertebral malformation. Here, the authors demonstrate that loss of dstyk leads to scoliosis in zebrafish due to dysregulated biogenesis of notochord vacuoles and that DSTYK is required for lysosome biogenesis through mTORC1 regulation.
- Xianding Sun
- , Yang Zhou
- & Lin Chen
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Article
| Open AccessGeneration of mesenchyme free intestinal organoids from human induced pluripotent stem cells
Human induced pluripotent stem cell-derived intestinal organoids (HIOs) are powerful tools to study development and diseases of the gastrointestinal tract. Here, the authors develop a directed differentiation protocol to generate mesenchyme-free HIOs that can be patterned towards proximal small intestine or colonic epithelium, and demonstrated their utility in modeling CFTR function.
- Aditya Mithal
- , Amalia Capilla
- & Gustavo Mostoslavsky
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Article
| Open AccessMonkeys mutant for PKD1 recapitulate human autosomal dominant polycystic kidney disease
Most cases of autosomal dominant polycystic kidney disease (ADPKD) are due to mutations in PKD1. Here, Tsukiyama et al. generate monkeys with mutations in PKD1 and show that animals recapitulate key pathological features of the human disease, suggesting these may provide insights into ADPKD pathogenesis and contribute to the development of future therapeutic strategies.
- Tomoyuki Tsukiyama
- , Kenichi Kobayashi
- & Masatsugu Ema
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Article
| Open AccessGenome-wide microhomologies enable precise template-free editing of biologically relevant deletion mutations
DNA repair by microhomology-mediated end joining creates precise deletions based on flanking microhomologies. Here the authors use CRISPR-Cas9 to recreate pathogenic deletion mutations using existing microhomologies in the human genome identified by their program MHcut.
- Janin Grajcarek
- , Jean Monlong
- & Knut Woltjen
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Article
| Open AccessCiliary exclusion of Polycystin-2 promotes kidney cystogenesis in an autosomal dominant polycystic kidney disease model
The molecular role of ciliary Polycystin-2 (PC2) in cyst formation and polycystic kidney disease (ADKPD) is unclear. Here, the authors identify a PC2 mutant lacking ciliary localisation but with active Ca2+ channel function in mice, that is sufficient to generate an ADPKD phenotype.
- Rebecca V. Walker
- , Jennifer L. Keynton
- & Dominic P. Norris
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Article
| Open AccessGenerating viable mice with heritable embryonically lethal mutations using the CRISPR-Cas9 system in two-cell embryos
Roughly 25% of mouse genes are embryonically lethal when knocked out, preventing the generation of viable mouse models. Here the authors use CRISPR-Cas9 to edit one blastomere of a two-cell embryo to generate viable chimeric mice.
- Yi Wu
- , Jing Zhang
- & Songlin Wang
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Article
| Open AccessSpinal neural tube closure depends on regulation of surface ectoderm identity and biomechanics by Grhl2
Loss or over-expression of Grainyhead-like transcription factors (Grhl) prevents closure of the neural tube but the mechanism underlying this is unclear. Here, the authors show that Grhl2 regulates murine posterior-neuropore closure via changes in the identity and biomechanics of the non-neural, surface ectoderm cells.
- Evanthia Nikolopoulou
- , Caroline S. Hirst
- & Nicholas D. E. Greene
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Article
| Open AccessTUBG1 missense variants underlying cortical malformations disrupt neuronal locomotion and microtubule dynamics but not neurogenesis
New mutations and genes associated with malformations of cortical development keep being identified, yet there is little known about the underlying cellular mechanisms controlling these impairments. Here, authors generate and characterize a heterozygous TUBG1 knock-in mouse model bearing one of these known mutations and show that TUBG1 mutation leads to the miss-positioning of neurons in the cortical wall due to migration, because of defective microtubules dynamics, and not proliferation defects during corticogenesis.
- Ekaterina L. Ivanova
- , Johan G. Gilet
- & Maria-Victoria Hinckelmann
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Article
| Open AccessHuman pre-valvular endocardial cells derived from pluripotent stem cells recapitulate cardiac pathophysiological valvulogenesis
There are few human models that can recapitulate valve development in vitro. Here, the authors derive human pre-valvular endocardial cells (HPVCs) from iPSCs and show they can recapitulate early valvulogenesis, and patient derived HPVCs have features of mitral valve prolapse and identified SHH dysregulation.
- Tui Neri
- , Emilye Hiriart
- & Michel Pucéat
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Article
| Open AccessSingle cell RNA-sequencing identifies a metabolic aspect of apoptosis in Rbf mutant
The function of the Retinoblastoma (Rb) protein is regulated by its cellular environment. Here, the authors perform single cell RNA-sequencing during Drosophila eye development and identify the impact of an Rbf mutation, which sensitises specific cells to apoptosis by changing metabolism.
- Majd M. Ariss
- , Abul B. M. M. K. Islam
- & Maxim V. Frolov
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Article
| Open AccessEpithelial cells release adenosine to promote local TNF production in response to polarity disruption
Epithelial stress can disrupt polarity and activate TNF and JNK signalling that contributes to inflammation and cell damage. Here, the authors show that disruption of apico-basal polarity leads to adenosine release, activating TNF and JNK and driving an inflammatory response during chronic stress.
- Ingrid Poernbacher
- & Jean-Paul Vincent
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Article
| Open AccessReciprocal inhibition of YAP/TAZ and NF-κB regulates osteoarthritic cartilage degradation
Inflammation can promote cartilage degradation by inducing matrix-degrading enzymes via NF-κB. Here the authors uncover reciprocal inhibition of Yap/Taz and NF-κB signaling though TAK1, and identify Yap activity as critical for maintenance of cartilage integrity in a mouse model of osteoarthritis.
- Yujie Deng
- , Jinqiu Lu
- & Kinglun Kingston Mak
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Article
| Open AccessDiscovery of a drug candidate for GLIS3-associated diabetes
GLIS3 mutations are associated with type 1, type 2, and neonatal diabetes. Here, the authors generate mono-hormonal glucose-responding pancreatic β-like cells in vitro and through a screen identify a drug that rescues pancreatic β-like cell death in GLIS3 mutants by inhibiting the abnormally activated TGFβ pathway.
- Sadaf Amin
- , Brandoch Cook
- & Shuibing Chen
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Article
| Open AccessDeficiency in class III PI3-kinase confers postnatal lethality with IBD-like features in zebrafish
The functions of the class III PI3-kinase (PIK3C3) in gut homeostasis and innate immunity are poorly understood. Here the authors show that PIK3C3-deficient zebrafishes develop intestinal injury and inflammation due to mislocalization of cell junction proteins.
- Shaoyang Zhao
- , Jianhong Xia
- & Xiaodong Shu
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Article
| Open AccessShort-term activation of the Jun N-terminal kinase pathway in apoptosis-deficient cells of Drosophila induces tumorigenesis
Jun N-terminal kinase (JNK) is necessary for development in tumours, indicating it may play tumour-promoting roles; however, the experimental analysis of the role of JNK in proliferation is hindered by its pro-apoptotic activity. Here the authors carry out experiments in Drosophila with genetic backgrounds that make cells refractory to apoptosis to definitely prove the JNK pathway contribution to tumorigenesis.
- Noelia Pinal
- , María Martín
- & Ginés Morata
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Article
| Open AccessActivin-dependent signaling in fibro/adipogenic progenitors causes fibrodysplasia ossificans progressiva
Fibrodysplasia ossificans progressiva is a severe disorder characterized by heterotopic ossification, and is caused by mutations in ACVR1. Here, the authors show that expression of mutant ACVR1 in fibro/adipogenic progenitors recapitulates disease progression, and that this can be halted by systemic inhibition of activin A in mice.
- John B. Lees-Shepard
- , Masakazu Yamamoto
- & David J. Goldhamer
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Article
| Open AccessZika virus infection in pregnant rhesus macaques causes placental dysfunction and immunopathology
Zika virus infection during pregnancy can result in birth defects, but underlying pathogenesis at the maternal-fetal interface is unclear. Here, the authors use non-invasive in vivo imaging of Zika-infected rhesus macaques and show that infection results in abnormal oxygen transport across the placenta.
- Alec J. Hirsch
- , Victoria H. J. Roberts
- & Daniel N. Streblow
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Article
| Open AccessEndoderm Jagged induces liver and pancreas duct lineage in zebrafish
The hepatopancreatic duct cells connect liver hepatocytes and pancreatic acinar cells to the intestine, but the mechanism for their lineage specification is unclear. Here, the authors reveal that Notch ligands Jagged1b and Jagged2b induce duct cell lineage in the liver and pancreas of the zebrafish.
- Danhua Zhang
- , Keith P. Gates
- & P. Duc Si Dong
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Article
| Open AccessMuscle pathology from stochastic low level DUX4 expression in an FSHD mouse model
Facioscapulohumeral muscular dystrophy is a severe myopathy that is caused by abnormal activation of DUX4, and for which a suitable mouse model does not exist. Here, the authors generate a novel mouse model with titratable expression of DUX4, and show that it recapitulates several features of the human pathology.
- Darko Bosnakovski
- , Sunny S. K. Chan
- & Michael Kyba
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Article
| Open AccessWnt signaling controls pro-regenerative Collagen XII in functional spinal cord regeneration in zebrafish
Following spinal injury in zebrafish, non-neural cells establish an extracellular matrix to promote axon re-growth but how this is regulated is unclear. Here, the authors show that Wnt/β-catenin signaling in fibroblast-like cells at a lesion activates axon re-growth via deposition of Collagen XII.
- Daniel Wehner
- , Themistoklis M. Tsarouchas
- & Catherina G. Becker
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Article
| Open AccessCellular interplay via cytokine hierarchy causes pathological cardiac hypertrophy in RAF1-mutant Noonan syndrome
The human congenital disorder Noonan Syndrome (NS) is caused by germ-line mutations that hyperactivate the RAS/ERK signalling pathway, and can feature pathologic cardiac enlargement. Here, the authors find that a complex cellular and molecular interplay involving a cytokine hierarchy underlies cardiac hypertrophy caused by a NS-associatedRafallele.
- Jiani C. Yin
- , Mathew J. Platt
- & Benjamin G. Neel
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Article
| Open AccessDefective Gpsm2/Gαi3 signalling disrupts stereocilia development and growth cone actin dynamics in Chudley-McCullough syndrome
Mutations inGPSM2cause a rare disease characterized by deafness and brain abnormalities. Here the authors show that Gpsm2 forms a molecular complex with a heterotrimeric G-protein subunit, whirlin and a myosin motor to regulate actin dynamics in neurons and auditory hair cell stereocilia.
- Stephanie A. Mauriac
- , Yeri E. Hien
- & Mireille Montcouquiol
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Article
| Open AccessThe pro-inflammatory signalling regulator Stat4 promotes vasculogenesis of great vessels derived from endothelial precursors
Stat4 is a transcription factor known to regulate pro-inflammatory signalling. Here, Menget al. show that Stat4 is not only regulating inflammation but it is also crucial for great vessels development and endothelial precursor proliferation in zebrafish, by inhibiting the expression of hdac3and counteracting the effect of Stat1a.
- Zhao-Zheng Meng
- , Wei Liu
- & Yong Zhou
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| Open AccessPlexins function in epithelial repair in both Drosophila and zebrafish
Plexins are semaphorin receptors and are well known for their roles in neuronal pathfinding. Here the authors describe a role for Plexin A in healing damaged epithelia in Drosophila and zebrafish. In Drosophila, Plexin A inhibits the GTPase Rap1 to allow epithelial remodelling to facilitate wound repair.
- Sa Kan Yoo
- , Heath G. Pascoe
- & Iswar K. Hariharan
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| Open AccessPrevention of Treacher Collins syndrome craniofacial anomalies in mouse models via maternal antioxidant supplementation
The TCOF1 gene is mutated in Treacher Collin's syndrome, a congenital craniofacial syndrome. Here, the authors show that Tcof1loss-of-function results in oxidative stress induced DNA damage and neuroepithelial cell death, and addition of antioxidants to pregnant mutant mice protected against these defects.
- Daisuke Sakai
- , Jill Dixon
- & Paul A. Trainor