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7. Characterization of the structure and control of the blood-nerve barrier identifies avenues for therapeutic delivery

Author

Malong, Liza, primary, Napoli, Ilaria, additional, Casal, Giulia, additional, White, Ian J., additional, Stierli, Salome, additional, Vaughan, Andrew, additional, Cattin, Anne-Laure, additional, Burden, Jemima J., additional, Hng, Keng I., additional, Bossio, Alessandro, additional, Flanagan, Adrienne, additional, Zhao, Hien T., additional, and Lloyd, Alison C., additional

Published
2023
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13. HDAC3 Regulates the Transition to the Homeostatic Myelinating Schwann Cell State

Author

Rosenberg, Laura H., Cattin, Anne-Laure, Fontana, Xavier, Harford-Wright, Elizabeth, Burden, Jemima J., White, Ian J., Smith, Jacob G., Napoli, Ilaria, Quereda, Victor, Policarpi, Cristina, Freeman, Jamie, Ketteler, Robin, Riccio, Antonella, and Lloyd, Alison C.

Subjects
Aging, Transcription, Genetic, HDACs, biogenesis, Sciatic Nerve, Article, Histone Deacetylases, Rats, Mice, Inbred C57BL, nervous system, lcsh:Biology (General), homeostasis, peripheral nerve, Animals, Schwann cells, neuropathy, lcsh:QH301-705.5, Myelin Sheath
Abstract

Summary The formation of myelinating Schwann cells (mSCs) involves the remarkable biogenic process, which rapidly generates the myelin sheath. Once formed, the mSC transitions to a stable homeostatic state, with loss of this stability associated with neuropathies. The histone deacetylases histone deacetylase 1 (HDAC1) and HDAC2 are required for the myelination transcriptional program. Here, we show a distinct role for HDAC3, in that, while dispensable for the formation of mSCs, it is essential for the stability of the myelin sheath once formed—with loss resulting in progressive severe neuropathy in adulthood. This is associated with the prior failure to downregulate the biogenic program upon entering the homeostatic state leading to hypertrophy and hypermyelination of the mSCs, progressing to the development of severe myelination defects. Our results highlight distinct roles of HDAC1/2 and HDAC3 in controlling the differentiation and homeostatic states of a cell with broad implications for the understanding of this important cell-state transition., Graphical Abstract, Highlights • HDAC3 is a positive regulator of myelin gene expression • Loss of HDAC3 expression in Schwann cells results in severe neuropathies • Myelination proceeds normally without HDAC3 but “overshoots” in adult mice • HDAC3 is required for myelinating Schwann cells to enter the homeostatic state, The entry of differentiating cells into a homeostatic state is poorly understood. Here, Rosenberg et al. show that a switch between HDAC1/2 and HDAC3 is responsible for the entry of myelinating Schwann cells into homeostasis with HDAC3−/− Schwann cells myelinating normally but “overshooting,” resulting in severe neuropathies in adult mice.

Published
2018

17. Sigma(sup)B ,odulates virulence determinant expression and stress resistance: characterization of a functional rsbU strain derived from Staphylococcus aureus 8325-4

Author

Horsburgh, Malcolm J., Aish, Joanne L., White, Ian J., Shaw, Les, Lithgow, James K., and Foster, Simon J.

Subjects
Staphylococcus aureus -- Genetic aspects, Virulence (Microbiology) -- Genetic aspects, Genetic regulation -- Analysis, Gene expression -- Physiological aspects, Gene expression -- Genetic aspects, Biological sciences
Abstract

Research describes the construction and phenotype of a functional rsbU regulator strain, SH1000, from Staphylococcus aureus 8325-4, to address the role of the accessory sigma factor sigma(sup)B in virulence in S. aureus. Results suggest that SarA regulator protein does not function as an effector in the overall sigma(sup)B-mediated effect on agr expression.

Published
2002

26. Fibroblastic Reticular Cells Control Conduit Matrix Deposition during Lymph Node Expansion

Author

Martinez, Victor G., primary, Pankova, Valeriya, additional, Krasny, Lukas, additional, Singh, Tanya, additional, Makris, Spyridon, additional, White, Ian J., additional, Benjamin, Agnesska C., additional, Dertschnig, Simone, additional, Horsnell, Harry L., additional, Kriston-Vizi, Janos, additional, Burden, Jemima J., additional, Huang, Paul H., additional, Tape, Christopher J., additional, and Acton, Sophie E., additional

Published
2019
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28. Conduit integrity is compromised during acute lymph node expansion

Author

Martinez, Victor G., primary, Pankova, Valeriya, additional, Krasny, Lukas, additional, Singh, Tanya, additional, White, Ian J., additional, Benjamin, Agnesska C., additional, Dertschnig, Simone, additional, Horsnell, Harry L., additional, Kriston-Vizi, Janos, additional, Burden, Jemima J., additional, Huang, Paul H., additional, Tape, Christopher J., additional, and Acton, Sophie E., additional

Published
2019
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30. Clathrin-mediated post-fusion membrane retrieval influences the exocytic mode of endothelial Weibel-Palade bodies

Author

Stevenson, Nicola L., White, Ian J., McCormack, Jessica J., Robinson, Christopher, Cutler, Daniel F., and Nightingale, Thomas D.

Subjects
Dynamin, Weibel-Palade Bodies, Human Umbilical Vein Endothelial Cells, Humans, Weibel-Palade bodies, Endothelium, Membrane Fusion, Endocytosis, Exocytosis, Clathrin, Research Article
Abstract

Weibel-Palade bodies (WPBs), the storage organelles of endothelial cells, are essential to normal haemostatic and inflammatory responses. Their major constituent protein is von Willebrand factor (VWF) which, following stimulation with secretagogues, is released into the blood vessel lumen as large platelet-catching strings. This exocytosis changes the protein composition of the cell surface and also results in a net increase in the amount of plasma membrane. Compensatory endocytosis is thought to limit changes in cell size and retrieve fusion machinery and other misplaced integral membrane proteins following exocytosis; however, little is known about the extent, timing, mechanism and precise function of compensatory endocytosis in endothelial cells. Using biochemical assays, live-cell imaging and correlative spinning-disk microscopy and transmission electron microscopy assays we provide the first in-depth high-resolution characterisation of this process. We provide a model of compensatory endocytosis based on rapid clathrin- and dynamin-mediated retrieval. Inhibition of this process results in a change of exocytic mode: WPBs then fuse with previously fused WPBs rather than the plasma membrane, leading, in turn, to the formation of structurally impaired tangled VWF strings. This article has an associated First Person interview with the first authors of the paper., Summary: Compensatory endocytosis plays key roles in Weibel-Palade body exocytosis. Inhibition of this process results in a change of exocytic mode and the release of von Willebrand factor as tangled strings.

Published
2017

31. Axonal autophagosome maturation defect through failure of ATG9A sorting underpins pathology in AP-4 deficiency syndrome.

Author

Ivankovic, Davor, Drew, James, Lesept, Flavie, White, Ian J., López Doménech, Guillermo, Tooze, Sharon A., and Kittler, Josef T.

Abstract

Adaptor protein (AP) complexes mediate key sorting decisions in the cell through selective incorporation of transmembrane proteins into vesicles. Little is known of the roles of AP-4, despite its loss of function leading to a severe early onset neurological disorder, AP-4 deficiency syndrome. Here we demonstrate an AP-4 epsilon subunit knockout mouse model that recapitulates characteristic neuroanatomical phenotypes of AP-4 deficiency patients. We show that ATG9A, critical for autophagosome biogenesis, is an AP-4 cargo, which is retained within the trans-Golgi network (TGN) in vivo and in culture when AP-4 function is lost. TGN retention results in depletion of axonal ATG9A, leading to defective autophagosome generation and aberrant expansions of the distal axon. The reduction in the capacity to generate axonal autophagosomes leads to defective axonal extension and de novo generation of distal axonal swellings containing accumulated ER, underlying the impaired axonal integrity in AP-4 deficiency syndrome. Abbreviations: AP: adaptor protein; AP4B1: adaptor-related protein complex AP-4, beta 1; AP4E1: adaptor-related protein complex AP-4, epsilon 1; ATG: autophagy-related; EBSS: Earle's balanced salt solution; ER: endoplasmic reticulum; GFAP: glial fibrillary acidic protein; GOLGA1/Golgin-97/GOLG97: golgi autoantigen, golgin subfamily a, 1; GOLGA2/GM130: golgi autoantigen, golgin subfamily a, 2; HSP: hereditary spastic paraplegia; LC3/MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; MAP2: microtubule-associated protein 2; MAPK8IP1/JIP1: mitogen-acitvated protein kinase 8 interacting protein 1; NEFH/NF200: neurofilament, heavy polypeptide; RBFOX3/NeuN (RNA binding protein, fox-1 homolog [C. elegans] 3); SQSTM1/p62: sequestosome 1; TGN: trans-Golgi network; WIPI2: WD repeat domain, phosphoinositide interacting protein 2 [ABSTRACT FROM AUTHOR]

Published
2020
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32. The regulation of the homeostasis and regeneration of peripheral nerve is distinct from the CNS and independent of a stem cell population

Author

Stierli, Salome, primary, Napoli, Ilaria, additional, White, Ian J., additional, Cattin, Anne-Laure, additional, Cabrejos, Anthony Monteza, additional, Calavia, Noelia Garcia, additional, Malong, Liza, additional, Ribeiro, Sara, additional, Nihouarn, Julie, additional, Williams, Richard, additional, Young, Kaylene M., additional, Richardson, William D., additional, and Lloyd, Alison C., additional

Published
2018
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34. Injury signals cooperate with Nf1 loss to relieve the tumor-suppressive environment of adult peripheral nerve

Author

Ribeiro, Sara, Napoli, Ilaria, White, Ian J., Parrinello, Simona, Flanagan, Adrienne M., Suter, Ueli, Parada, Luis F., and Lloyd, Alison C.

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, Neurofibromatosis 1, Neurofibromin 1, MAP Kinase Signaling System, Mice, Transgenic, Cell Growth Processes, eye diseases, nervous system diseases, Mice, Inbred C57BL, Mice, lcsh:Biology (General), nervous system, Peripheral Nerve Injuries, Genes, Neurofibromatosis 1, Animals, Schwann Cells, lcsh:QH301-705.5, neoplasms
Abstract

Schwann cells are highly plastic cells that dedifferentiate to a progenitor-like state following injury. However, deregulation of this plasticity, may be involved in the formation of neurofibromas, mixed-cell tumors of Schwann cell (SC) origin that arise upon loss of NF1. Here, we show that adult myelinating SCs (mSCs) are refractory to Nf1 loss. However, in the context of injury, Nf1-deficient cells display opposing behaviors along the wounded nerve; distal to the injury, Nf1−/− mSCs redifferentiate normally, whereas at the wound site Nf1−/− mSCs give rise to neurofibromas in both Nf1+/+ and Nf1+/− backgrounds. Tracing experiments showed that distinct cell types within the tumor derive from Nf1-deficient SCs. This model of neurofibroma formation demonstrates that neurofibromas can originate from adult SCs and that the nerve environment can switch from tumor suppressive to tumor promoting at a site of injury. These findings have implications for both the characterization and treatment of neurofibromas., Cell Reports, 5 (1), ISSN:2666-3864, ISSN:2211-1247

Published
2013

35. Type II PI4-kinases control Weibel-Palade body biogenesis and von Willebrand factor structure in human endothelial cells

Author

da Silva, Mafalda Lopes, Connor, Marie N. O ’, Kriston-Vizi, Janos, White, Ian J., Al-Shawi, Raya, Simons, J. Paul, Mössinger, Julia, Cutler, Daniel F., and Haucke, Volker

Subjects
Weibel-Palade body, Phosphatidylinositol 4-kinase beta, Phosphatidylinositol 4-kinase alpha, Von Willebrand factor
Abstract

Weibel-Palade bodies (WPBs) are endothelial storage organelles that mediate the release of molecules involved in thrombosis, inflammation and angiogenesis, including the pro-thrombotic glycoprotein von Willebrand factor (VWF). Although many protein components required for WPB formation and function have been identified, the role of lipids is almost unknown. We examined two key phosphatidylinositol kinases that control phosphatidylinositol 4-phosphate levels at the trans-Golgi network, the site of WPB biogenesis. RNA interference of the type II phosphatidylinositol 4-kinases PI4KIIα and PI4KIIβ in primary human endothelial cells leads to formation of an increased proportion of short WPB with perturbed packing of VWF, as exemplified by increased exposure of antibody-binding sites. When stimulated with histamine, these cells release normal levels of VWF yet, under flow, form very few platelet-catching VWF strings. In PI4KIIα-deficient mice, immuno-microscopy revealed that VWF packaging is also perturbed and these mice exhibit increased blood loss after tail cut compared to controls. This is the first demonstration that lipid kinases can control the biosynthesis of VWF and the formation of WPBs that are capable of full haemostatic function.

Published
2016

37. Assessing the effects of mitofusin 2 deficiency in the adult heart using 3D electron tomography

Author

Beikoghli Kalkhoran, Siavash, primary, Hall, Andrew R., additional, White, Ian J., additional, Cooper, Jackie, additional, Fan, Qiao, additional, Ong, Sang-Bing, additional, Hernández-Reséndiz, Sauri, additional, Cabrera-Fuentes, Hector, additional, Chinda, Kroekkiat, additional, Chakraborty, Bibhas, additional, Dorn, Gerald W., additional, Yellon, Derek M., additional, and Hausenloy, Derek J., additional

Published
2017
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41. A Central Role for the ERK-Signaling Pathway in Controlling Schwann Cell Plasticity and Peripheral Nerve Regeneration In Vivo

Author

Napoli, Ilaria, primary, Noon, Luke A., additional, Ribeiro, Sara, additional, Kerai, Ajay P., additional, Parrinello, Simona, additional, Rosenberg, Laura H., additional, Collins, Melissa J., additional, Harrisingh, Marie C., additional, White, Ian J., additional, Woodhoo, Ashwin, additional, and Lloyd, Alison C., additional

Published
2012
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42. Pathophysiology of Dyt1-Tor1adystonia in mice is mediated by spinal neural circuit dysfunction

Author

Pocratsky, Amanda M., Nascimento, Filipe, Özyurt, M. Görkem, White, Ian J., Sullivan, Roisin, O’Callaghan, Benjamin J., Smith, Calvin C., Surana, Sunaina, Beato, Marco, and Brownstone, Robert M.

Abstract

Dystonia, a neurological disorder defined by abnormal postures and disorganized movements, is considered to be a neural circuit disorder with dysfunction arising within and between multiple brain regions. Given that spinal neural circuits constitute the final pathway for motor control, we sought to determine their contribution to this movement disorder. Focusing on the most common inherited form of dystonia in humans, DYT1-TOR1A, we generated a conditional knockout of the torsin family 1 member A (Tor1a) gene in the mouse spinal cord and dorsal root ganglia (DRG). We found that these mice recapitulated the phenotype of the human condition, developing early-onset generalized torsional dystonia. Motor signs emerged early in the mouse hindlimbs before spreading caudo-rostrally to affect the pelvis, trunk, and forelimbs throughout postnatal maturation. Physiologically, these mice bore the hallmark features of dystonia, including spontaneous contractions at rest and excessive and disorganized contractions, including cocontractions of antagonist muscle groups, during voluntary movements. Spontaneous activity, disorganized motor output, and impaired monosynaptic reflexes, all signs of human dystonia, were recorded from isolated mouse spinal cords from these conditional knockout mice. All components of the monosynaptic reflex arc were affected, including motor neurons. Given that confining the Tor1aconditional knockout to DRG did not lead to early-onset dystonia, we conclude that the pathophysiological substrate of this mouse model of dystonia lies in spinal neural circuits. Together, these data provide new insights into our current understanding of dystonia pathophysiology.

Published
2023
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