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Anna-Karina B Maier, Sabrina Klein, Norbert Kociok, Aline I Riechardt, Enken Gundlach, Nadine Reichhart, Olaf Strauß, Antonia M Joussen
Purpose: Netrin-4, a secreted protein, is found in the basement membrane of blood vessels and acts as a key regulator of angiogenesis. Here we investigated the role of Netrin-4 in the mouse-model of suture-induced corneal hem- and lymphangiogenesis. Methods: Corneal hem- and lymphangiogenesis were induced in Netrin-4-deficient (Ntn4-/-) and wild-type (WT) mice by placing three 11-0 nylon sutures intrastromally. Fourteen days after suturing, the vascularized area was analyzed via corneal flat mount immunohistochemistry...
March 1, 2017: Investigative Ophthalmology & Visual Science
Xin-Peng Dun, David B Parkinson
Netrin-1 was the first axon guidance molecule to be discovered in vertebrates and has a strong chemotropic function for axonal guidance, cell migration, morphogenesis and angiogenesis. It is a secreted axon guidance cue that can trigger attraction by binding to its canonical receptors Deleted in Colorectal Cancer (DCC) and Neogenin or repulsion through binding the DCC/Uncoordinated (Unc5) A-D receptor complex. The crystal structures of Netrin-1/receptor complexes have recently been revealed. These studies have provided a structure based explanation of Netrin-1 bi-functionality...
February 24, 2017: International Journal of Molecular Sciences
Catalina P Prieto, María Carolina Ortiz, Andrea Villanueva, Cynthia Villarroel, Sandra S Edwards, Matías Elliott, José Lattus, Sócrates Aedo, Daniel Meza, Pablo Lois, Verónica Palma
BACKGROUND: Angiogenesis, the process in which new blood vessels are formed from preexisting ones, is highly dependent on the presence of classical angiogenic factors. Recent evidence suggests that axonal guidance proteins and their receptors can also act as angiogenic regulators. Netrin, a family of laminin-like proteins, specifically Netrin-1 and 4, act via DCC/Neogenin-1 and UNC5 class of receptors to promote or inhibit angiogenesis, depending on the physiological context. METHODS: Mesenchymal stem cells secrete a broad set of classical angiogenic factors...
February 28, 2017: Stem Cell Research & Therapy
Trevor W Stone, L Gail Darlington
Several toxins are known which account for the ability of some bacteria to initiate or promote carcinogenesis. These ideas are summarised and evidence is discussed for more specific mechanisms involving chymotrypsin and the bacterial chymotryptic enzyme subtilisin. Subtilisin and Bacillus subtilis are present in the gut and environment and both are used commercially in agriculture, livestock rearing and meat processing. The enzymes deplete cells of tumour suppressors such as deleted in colorectal cancer (DCC) and neogenin, so their potential presence in the food chain might represent an important link between diet and cancer...
February 25, 2017: Cellular and Molecular Life Sciences: CMLS
Lin Wang, Zhiyu Liu, Herong Shi, Jun Liu
The highly conserved bone morphogenetic protein (BMP) signaling pathway regulates many developmental and homeostatic processes. While the core components of the BMP pathway have been well studied, much research is needed for understanding the mechanisms involved in the precise spatiotemporal control of BMP signaling in vivo. Here, we provide evidence that two paralogous and evolutionarily conserved tetraspanins, TSP-12 and TSP-14, function redundantly to promote BMP signaling in C. elegans. We further show that the ADAM10 (a disintegrin and metalloprotease 10) ortholog SUP-17 also functions to promote BMP signaling, and that TSP-12 can bind to and promote the cell surface localization of SUP-17...
January 2017: PLoS Genetics
Andrea A Villanueva, Paulina Falcón, Natalie Espinoza, Luis Solano R, Luis A Milla, Esther Hernandez-SanMiguel, Vicente A Torres, Pilar Sanchez-Gomez, Verónica Palma
Neogenin-1 (NEO1) is a transmembrane receptor involved in axonal guidance, angiogenesis, neuronal cell migration and cell death, during both embryonic development and adult homeostasis. It has been described as a dependence receptor, because it promotes cell death in the absence of its ligands (Netrin and Repulsive Guidance Molecule (RGM) families) and cell survival when they are present. Although NEO1 and its ligands are involved in tumor progression, their precise role in tumor cell survival and migration remain unclear...
February 7, 2017: Oncotarget
Kyoung Hee Choi, Seon Hwa Hong, Hye Ran Lee, Hoon Taek Lee, Jae Ho Lee, Sang Jin Lee
No abstract text is available yet for this article.
January 22, 2017: Biochemical and Biophysical Research Communications
Jie Chen, Cindy Laramore, Michael I Shifman
Spinal cord injury (SCI) in mammals leads to permanent loss of function because axons do not regenerate in the central nervous system (CNS). To date, treatments based on neutralizing inhibitory environmental cues, such as the myelin-associated growth inhibitors and chondroitin sulfate proteoglycans, or on adding neurotrophic factors, have had limited success in enhancing regeneration. Published studies suggested that multiple axon guidance cues (repulsive guidance molecule (RGM) family, semaphorins, ephrins, and netrins) persist in adult animals, and that their expression is upregulated after CNS injury...
January 26, 2017: Neuroscience
Caroline M Forrest, Kara McNair, Maria C J Vincenten, L Gail Darlington, Trevor W Stone
BACKGROUND: The related tumour suppressor proteins Deleted in Colorectal Cancer (DCC) and neogenin are absent or weakly expressed in many cancers, whereas their insertion into cells suppresses oncogenic behaviour. Serine proteases influence the initiation and progression of cancers although the mechanisms are unknown. METHODS: The effects of environmental (bacterial subtilisin) and endogenous mammalian (chymotrypsin) serine proteases were examined on protein expression in fresh, normal tissue and human neuroblastoma and mammary adenocarcinoma lines...
October 6, 2016: BMC Cancer
Jiangfeng Liu, Weiling Wang, Ming Liu, Limin Su, Hong Zhou, Yin Xia, Jianhua Ran, Herbert Y Lin, Baoxue Yang
Autosomal dominant polycystic kidney disease (ADPKD) is a monogenetic disease that still lacks effective therapy. Repulsive guidance molecule b (RGMb), a co-receptor for bone morphogenetic proteins (BMPs) and a ligand for neogenin, is expressed in renal tubular epithelial cells. Previous studies showed that RGMb plays negative roles in several types of tumors and prevents the immune system from over activation. The present study was designed to explore the effects of RGMb in ADPKD development. We found that expression of RGMb in kidney was less in PKD mice than wild-type mice...
December 2016: Cellular Signalling
Leo Boneschansker, Hironao Nakayama, Michele Eisenga, Johannes Wedel, Michael Klagsbrun, Daniel Irimia, David M Briscoe
Netrin-1 is a neuronal guidance cue that regulates cellular activation, migration, and cytoskeleton rearrangement in multiple cell types. It is a chemotropic protein that is expressed within tissues and elicits both attractive and repulsive migratory responses. Netrin-1 has recently been found to modulate the immune response via the inhibition of neutrophil and macrophage migration. However, the ability of Netrin-1 to interact with lymphocytes and its in-depth effects on leukocyte migration are poorly understood...
August 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Jae H Lee, Yong Ii Cho, Sung S Choi, Hae-Won Kim, Churl K Min, Sang J Lee
Gene silencing and overexpression techniques are instrumental for the identification of genes involved in embryonic development. Direct target gene modification in preimplantation embryos provides a means to study the underlying mechanisms of genes implicated in, for instance, cellular differentiation into the trophectoderm (TE) and the inner cell mass (ICM). Here, we describe a protocol that examines the role of neogenin as an authentic receptor for initial cell fate determination in preimplantation mouse embryos...
2016: Journal of Visualized Experiments: JoVE
Zhihui Huang, Dong Sun, Jin-Xia Hu, Fu-Lei Tang, Dae-Hoon Lee, Ying Wang, Guoqing Hu, Xiao-Juan Zhu, Jiliang Zhou, Lin Mei, Wen-Cheng Xiong
UNLABELLED: Neogenin, a DCC (deleted in colorectal cancer) family receptor, is highly expressed in neural stem cells (NSCs). However, its function in NSCs remains to be explored. Here we provide in vitro and in vivo evidence for neogenin's function in NSCs to promote neocortical astrogliogenesis, but not self-renewal or neural differentiation. Mechanistically, neogenin in neocortical NSCs was required for BMP2 activation of YAP (yes associated protein). The active/nuclear YAP stabilized phospho-Smad1/5/8 and was necessary for BMP2 induction of astrocytic differentiation...
May 25, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Joseph Wai Keung Kam, Emilie Dumontier, Christopher Baim, Alexandra C Brignall, David Mendes da Silva, Mitra Cowan, Timothy E Kennedy, Jean-François Cloutier
Cellular interactions are key for the differentiation of distinct cell types within developing epithelia, yet the molecular mechanisms engaged in these interactions remain poorly understood. In the developing olfactory epithelium (OE), neural stem/progenitor cells give rise to odorant-detecting olfactory receptor neurons (ORNs) and glial-like sustentacular (SUS) cells. Here, we show in mice that the transmembrane receptor neogenin (NEO1) and its membrane-bound ligand RGMB control the balance of neurons and glial cells produced in the OE...
May 1, 2016: Development
Ningning Zhao, Julia E Maxson, Richard H Zhang, Mastura Wahedi, Caroline A Enns, An-Sheng Zhang
Hemojuvelin (HJV) regulates iron homeostasis by direct interaction with bone morphogenetic protein (BMP) ligands to induce hepcidin expression through the BMP signaling pathway in the liver. Crystallography studies indicate that HJV can simultaneously bind to both BMP2 and the ubiquitously expressed cell surface receptor neogenin. However, the role of the neogenin-HJV interaction in the function of HJV is unknown. Here we identify a mutation in HJV that specifically lowers its interaction with neogenin. Expression of this mutant Hjv in the liver of Hjv(-/-) mice dramatically attenuated its induction of BMP signaling and hepcidin mRNA, suggesting that interaction with neogenin is critical for the iron regulatory function of HJV...
June 3, 2016: Journal of Biological Chemistry
Natalie K Lee, Ka Wai Fok, Amanda White, Nicole H Wilson, Conor J O'Leary, Hayley L Cox, Magdalene Michael, Alpha S Yap, Helen M Cooper
To maintain tissue integrity during epithelial morphogenesis, adherens junctions (AJs) must resist the mechanical stresses exerted by dynamic tissue movements. Junctional stability is dependent on actomyosin contractility within the actin ring. Here we describe a novel function for the axon guidance receptor, Neogenin, as a key component of the actin nucleation machinery governing junctional stability. Loss of Neogenin perturbs AJs and attenuates junctional tension. Neogenin promotes actin nucleation at AJs by recruiting the Wave regulatory complex (WRC) and Arp2/3...
2016: Nature Communications
Preethne Böser, Yulia Mordashova, Mark Maasland, Isabel Trommer, Helga Lorenz, Mathias Hafner, Dietmar Seemann, Bernhard K Mueller, Andreas Popp
Hepcidin was originally detected as a liver peptide with antimicrobial activity and it functions as a central regulator in the systemic iron metabolism. Consequently suppression of hepcidin leads to iron accumulation in the liver. AbbVie developed a monoclonal antibody ([mAb]; repulsive guidance molecule [RGMa/c] mAb) that downregulates hepcidin expression by influencing the RGMc/bone morphogenetic protein (BMP)/neogenin receptor complex and causes iron deposition in the liver. In a dose range finding study with RGMa/c mAb, rats were treated with different dose levels for a total of 4 weekly doses...
February 2016: Toxicologic Pathology
Kana Harada, Yuki Fujita, Toshihide Yamashita
The repulsive guidance molecule-a (RGMa) is a membrane-associated glycoprotein that has diverse functions in the developing and adult central nervous system. Here, we show that RGMa suppresses new blood vessel formation. Treatment of human umbilical artery endothelial cells (HUAEC) on Matrigel with recombinant RGMa inhibits vascular endothelial growth factor (VEGF)-induced and VEGF-independent tubular formation and migration. RGMa enhances adhesion presumably through dephosphorylation of focal adhesion kinase (FAK) at tyrosine-397...
January 22, 2016: Biochemical and Biophysical Research Communications
Yohei Shinmyo, M Asrafuzzaman Riyadh, Giasuddin Ahmed, Iftekhar Bin Naser, Mahmud Hossain, Hirohide Takebayashi, Hiroshi Kawasaki, Kunimasa Ohta, Hideaki Tanaka
The thalamocortical tract carries sensory information to the neocortex. It has long been recognized that the neocortical pioneer axons of subplate neurons are essential for thalamocortical development. Herein we report that an axon guidance cue, draxin, is expressed in early-born neocortical neurons, including subplate neurons, and is necessary for thalamocortical development. In draxin(-/-) mice, thalamocortical axons do not enter the neocortex. This phenotype is sufficiently rescued by the transgenic expression of draxin in neocortical neurons...
2015: Nature Communications
Susan van Erp, Dianne M A van den Heuvel, Yuki Fujita, Ross A Robinson, Anita J C G M Hellemons, Youri Adolfs, Eljo Y Van Battum, Anna M Blokhuis, Marijn Kuijpers, Jeroen A A Demmers, Håkan Hedman, Casper C Hoogenraad, Christian Siebold, Toshihide Yamashita, R Jeroen Pasterkamp
Many guidance receptors are proteolytically cleaved by membrane-associated metalloproteases of the ADAM family, leading to the shedding of their ectodomains. Ectodomain shedding is crucial for receptor signaling and function, but how this process is controlled in neurons remains poorly understood. Here, we show that the transmembrane protein Lrig2 negatively regulates ADAM-mediated guidance receptor proteolysis in neurons. Lrig2 binds Neogenin, a receptor for repulsive guidance molecules (RGMs), and prevents premature Neogenin shedding by ADAM17 (TACE)...
December 7, 2015: Developmental Cell
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