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1.
Dev Biol ; 462(2): 141-151, 2020 06 15.
Article in English | MEDLINE | ID: mdl-32197891

ABSTRACT

Organs mainly attain their size by cell growth and proliferation, but sometimes also grow through recruitment of undifferentiated cells. Here we investigate the participation of cell recruitment in establishing the pattern of Vestigial (Vg), the product of the wing selector gene in Drosophila. We find that the Vg pattern overscales along the dorsal-ventral (DV) axis of the wing imaginal disc, i.e., it expands faster than the DV length of the pouch. The overscaling of the Vg pattern cannot be explained by differential proliferation, apoptosis, or oriented-cell divisions, but can be recapitulated by a mathematical model that explicitly considers cell recruitment. When impairing cell recruitment genetically, we find that the Vg pattern almost perfectly scales and adult wings are approximately 20% smaller. Conversely, impairing cell proliferation results in very small wings, suggesting that cell recruitment and cell proliferation additively contribute to organ growth in this system. Furthermore, using fluorescent reporter tools, we provide direct evidence that cell recruitment is initiated between early and mid third-instar larval development. Altogether, our work quantitatively shows when, how, and by how much cell recruitment shapes the Vg pattern and drives growth of the Drosophila wing.


Subject(s)
Body Patterning/genetics , Drosophila Proteins/genetics , Nuclear Proteins/genetics , Wings, Animal/growth & development , Animals , Cell Division , Drosophila Proteins/metabolism , Drosophila melanogaster/embryology , Drosophila melanogaster/genetics , Gene Expression Regulation, Developmental/genetics , Imaginal Discs/growth & development , Nuclear Proteins/metabolism , Signal Transduction , Transcription Factors/metabolism , Wnt1 Protein/metabolism
2.
Ann Rheum Dis ; 76(2): 468-472, 2017 Feb.
Article in English | MEDLINE | ID: mdl-27566796

ABSTRACT

OBJECTIVES: Familial chilblain lupus is a monogenic form of cutaneous lupus erythematosus caused by loss-of-function mutations in the nucleases TREX1 or SAMHD1. In a family without TREX1 or SAMHD1 mutation, we sought to determine the causative gene and the underlying disease pathology. METHODS: Exome sequencing was used for disease gene identification. Structural analysis was performed by homology modelling and docking simulations. Type I interferon (IFN) activation was assessed in cells transfected with STING cDNA using an IFN-ß reporter and Western blotting. IFN signatures in patient blood in response to tofacitinib treatment were measured by RT-PCR of IFN-stimulated genes. RESULTS: In a multigenerational family with five members affected with chilblain lupus, we identified a heterozygous mutation of STING, a signalling molecule in the cytosolic DNA sensing pathway. Structural and functional analyses indicate that mutant STING enhances homodimerisation in the absence of its ligand cGAMP resulting in constitutive type I IFN activation. Treatment of two affected family members with the Janus kinase (JAK) inhibitor tofacitinib led to a marked suppression of the IFN signature. CONCLUSIONS: A heterozygous gain-of-function mutation in STING can cause familial chilblain lupus. These findings expand the genetic spectrum of type I IFN-dependent disorders and suggest that JAK inhibition may be of therapeutic value.


Subject(s)
Chilblains/genetics , Lupus Erythematosus, Cutaneous/genetics , Membrane Proteins/genetics , Adult , Blotting, Western , Chilblains/drug therapy , Chilblains/immunology , Chilblains/pathology , Family , Female , Greece , Humans , Interferon Type I/immunology , Interferon-beta/immunology , Lupus Erythematosus, Cutaneous/drug therapy , Lupus Erythematosus, Cutaneous/immunology , Lupus Erythematosus, Cutaneous/pathology , Male , Microscopic Angioscopy , Molecular Docking Simulation , Mutation , Pedigree , Piperidines/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/therapeutic use , Pyrroles/therapeutic use , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Skin/pathology
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