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  • 1
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    FGF signalling regulates bone growth through autophagy (2015)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2015-11-26
    Description: Skeletal growth relies on both biosynthetic and catabolic processes. While the role of the former is clearly established, how the latter contributes to growth-promoting pathways is less understood. Macroautophagy, hereafter referred to as autophagy, is a catabolic process that plays a fundamental part in tissue homeostasis. We investigated the role of autophagy during bone growth, which is mediated by chondrocyte rate of proliferation, hypertrophic differentiation and extracellular matrix (ECM) deposition in growth plates. Here we show that autophagy is induced in growth-plate chondrocytes during post-natal development and regulates the secretion of type II collagen (Col2), the major component of cartilage ECM. Mice lacking the autophagy related gene 7 (Atg7) in chondrocytes experience endoplasmic reticulum storage of type II procollagen (PC2) and defective formation of the Col2 fibrillary network in the ECM. Surprisingly, post-natal induction of chondrocyte autophagy is mediated by the growth factor FGF18 through FGFR4 and JNK-dependent activation of the autophagy initiation complex VPS34-beclin-1. Autophagy is completely suppressed in growth plates from Fgf18(-/-) embryos, while Fgf18(+/-) heterozygous and Fgfr4(-/-) mice fail to induce autophagy during post-natal development and show decreased Col2 levels in the growth plate. Strikingly, the Fgf18(+/-) and Fgfr4(-/-) phenotypes can be rescued in vivo by pharmacological activation of autophagy, pointing to autophagy as a novel effector of FGF signalling in bone. These data demonstrate that autophagy is a developmentally regulated process necessary for bone growth, and identify FGF signalling as a crucial regulator of autophagy in chondrocytes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cinque, Laura -- Forrester, Alison -- Bartolomeo, Rosa -- Svelto, Maria -- Venditti, Rossella -- Montefusco, Sandro -- Polishchuk, Elena -- Nusco, Edoardo -- Rossi, Antonio -- Medina, Diego L -- Polishchuk, Roman -- De Matteis, Maria Antonietta -- Settembre, Carmine -- England -- Nature. 2015 Dec 10;528(7581):272-5. doi: 10.1038/nature16063. Epub 2015 Nov 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei, 34, 80078 Pozzuoli (NA), Italy. ; Dulbecco Telethon Institute, Via Campi Flegrei, 34, 80078 Pozzuoli (NA), Italy. ; Medical Genetics Unit, Department of Medical and Translational Science, Federico II University, Via Pansini 5, 80131 Naples, Italy. ; Department of Molecular Medicine, Biochemistry Unit, University of Pavia, 27100 Pavia, Italy.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26595272" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autophagy/genetics/*physiology ; Bone Development/genetics/*physiology ; Cell Differentiation ; Cell Proliferation ; Cells, Cultured ; Chondrocytes/cytology/metabolism ; Collagen Type II/secretion ; Embryo, Mammalian ; Extracellular Matrix/genetics ; Fibroblast Growth Factors/*genetics/metabolism ; Growth Plate/cytology/metabolism ; MAP Kinase Signaling System ; Mice ; Microtubule-Associated Proteins/genetics/metabolism ; Receptor, Fibroblast Growth Factor, Type 4/genetics/metabolism ; *Signal Transduction
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Systemic inflammation and neurodegeneration in a mouse model of multiple sulfatase deficiency (2007)
    National Academy of Sciences
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    Publication Date: 2007-03-06
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 3
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    Tbx1 regulates brain vascularization (2013)
    Oxford University Press
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    Publication Date: 2013-12-11
    Description: The transcription factor TBX1 is the major gene involved in 22q11.2 deletion syndrome (22q11.2DS). Using mouse models of these diseases, we have previously shown that TBX1 activates VEGFR3 in endothelial cells (EC), and that this interaction is critical for the development of the lymphatic vasculature. In this study, we show that TBX1 regulates brain angiogenesis. Using loss-of-function genetics and molecular approaches, we show that TBX1 regulates the VEGFR3 and DLL4 genes in brain ECs. In mice, loss of TBX1 causes global brain vascular defects, comprising brain vessel hyperplasia, enhanced angiogenic sprouting and vessel network disorganization. This phenotype is recapitulated in EC-specific Tbx1 conditional mutants and in an EC-only 3-dimensional cell culture system (matrigel), indicating that the brain vascular phenotype is cell autonomous. Furthermore, EC-specific conditional Tbx1 mutants have poorly perfused brain vessels and brain hypoxia, indicating that the expanded vascular network is functionally impaired. In EC-matrigel cultures, a Notch1 agonist is able to partially rescue microtubule hyperbranching induced by TBX1 knockdown. Thus, we have identified a novel transcriptional regulator of angiogenesis that exerts its effect in brain by negatively regulating angiogenesis through the DLL4/Notch1–VEGFR3 regulatory axis. Given the similarity of the phenotypic consequences of TBX1 mutation in humans and mice, this unexpected role of TBX1 in murine brain vascularization should stimulate clinicians to search for brain microvascular anomalies in 22q11.2DS patients and to evaluate whether some of the anatomical and functional brain anomalies in patients may have a microvascular origin.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 4
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    Transcriptional activation of RagD GTPase controls mTORC1 and promotes cancer growth (2017)
    American Association for the Advancement of Science (AAAS)
    In: Science
    Details
    Publication Date: 2017-06-16
    Description: The mechanistic target of rapamycin complex 1 (mTORC1) is recruited to the lysosome by Rag guanosine triphosphatases (GTPases) and regulates anabolic pathways in response to nutrients. We found that MiT/TFE transcription factors—master regulators of lysosomal and melanosomal biogenesis and autophagy—control mTORC1 lysosomal recruitment and activity by directly regulating the expression of RagD. In mice, this mechanism mediated adaptation to food availability after starvation and physical exercise and played an important role in cancer growth. Up-regulation of MiT/TFE genes in cells and tissues from patients and murine models of renal cell carcinoma, pancreatic ductal adenocarcinoma, and melanoma triggered RagD-mediated mTORC1 induction, resulting in cell hyperproliferation and cancer growth. Thus, this transcriptional regulatory mechanism enables cellular adaptation to nutrient availability and supports the energy-demanding metabolism of cancer cells.
    Keywords: Genetics
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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