Staff member

Vanessa Gil Fernández

Postdoctoral Researcher
Molecular and Cellular Neurobiotechnology
+34 934 031 185
Staff member publications

Gutiérrez-Franco, Ana, Eixarch, Herena, Costa, Carme, Gil, Vanessa, Castillo, Mireia, Calvo-Barreiro, Laura, Montalban, Xavier, Del Río, José A., Espejo, Carmen, (2017). Semaphorin 7A as a potential therapeutic target for multiple sclerosis Molecular Neurobiology 54, (6), 4820-4831

Semaphorin 7A (sema7A) is classified as an immune semaphorin with dual functions in the immune system and in the central nervous system (CNS). These molecules are of interest due to their potential role in multiple sclerosis (MS), which is a chronic demyelinating and neurodegenerative disease of autoimmune origin. In this study, we elucidated the role of sema7A in neuroinflammation using both in vitro and in vivo experimental models. In an in vitro model of neuroinflammation, using cerebellar organotypic slice cultures, we observed that challenge with lipopolysaccharide (LPS) endotoxin did not affect demyelination or cell death in sema7A-deficient cultures compared to wild-type cultures. Moreover, the in vivo outcome of experimental autoimmune encephalomyelitis (EAE) in sema7A-deficient mice was altered in an antigen- and adjuvant-dose-dependent manner, while no differences were observed in the wild-type counterparts. Altogether, these results indicate that sema7A is involved in peripheral immunity and CNS inflammation in MS pathogenesis. Indeed, these data suggest that sema7A might be a potential therapeutic target to treat MS and autoimmune conditions.

Tomas-Roig, J., Piscitelli, F., Gil, V., del Río, J. A., Moore, T. P., Agbemenyah, H., Salinas-Riester, G., Pommerenke, C., Lorenzen, S., Beißbarth, T., Hoyer-Fender, S., Di Marzo, V., Havemann-Reinecke, U., (2016). Social defeat leads to changes in the endocannabinoid system: An overexpression of calreticulin and motor impairment in mice Behavioural Brain Research 303, 34-43

Prolonged and sustained stimulation of the hypothalamo-pituitary-adrenal axis have adverse effects on numerous brain regions, including the cerebellum. Motor coordination and motor learning are essential for animal and require the regulation of cerebellar neurons. The G-protein-coupled cannabinoid CB1 receptor coordinates synaptic transmission throughout the CNS and is of highest abundance in the cerebellum. Accordingly, the aim of this study was to investigate the long-lasting effects of chronic psychosocial stress on motor coordination and motor learning, CB1 receptor expression, endogenous cannabinoid ligands and gene expression in the cerebellum. After chronic psychosocial stress, motor coordination and motor learning were impaired as indicated the righting reflex and the rota-rod. The amount of the endocannabinoid 2-AG increased while CB1 mRNA and protein expression were downregulated after chronic stress. Transcriptome analysis revealed 319 genes differentially expressed by chronic psychosocial stress in the cerebellum; mainly involved in synaptic transmission, transmission of nerve impulse, and cell-cell signaling. Calreticulin was validated as a stress candidate gene. The present study provides evidence that chronic stress activates calreticulin and might be one of the pathological mechanisms underlying the motor coordination and motor learning dysfunctions seen in social defeat mice.

Keywords: Psychosocial stress, Cerebellum, Calreticulin, Endocannabinoid system, Behavior, RNA seq.

Tomas Roig, J., Piscitelli, F., Gil, V., Havemann Reinecke, U., (2015). Chronic psychosocial stress and endocannabinoid system interact to affect the transcription of SLC6A4, in the mouse corticostriatal circuits European Neuropsychopharmacology 28th ECNP Congress , Elsevier (Amsterdam, The Netherlands) 25, (Supplement 2), P.1.a.001

Vulnerability for psychosis is determined by the interacting contributions of multiple genetic and environmental factors. Dysregulation of corticostriatal circuitry has long been thought to be critical in the etiology of psychotic disorders. Psychosocial stress is known to have a great influence on brain function and behavior. In response to persistent stress exposure, chronic glucocorticoid exposure appears to have adverse effects on numerous brain regions. Glucocorticoid receptor (GR) functioning is regulated in part by FKBP5 and its activity modulates serotoninergic neurotransmission. Extracellular serotonin reuptake is monitored by the serotonin transporter gene SLC6A4. Cannabinoid CB1 receptor mediates glucocorticoid effects and it’s highly expressed in the corticostriatal circuits.

Bribián, A., Nocentini, S., Llorens, F., Gil, V., Mire, E., Reginensi, D., Yoshida, Y., Mann, F., Del Río, J. A., (2014). Sema3E/PlexinD1 regulates the migration of hem-derived Cajal-Retzius cells in developing cerebral cortex Nature Communications 5, 4265

During the development of the cerebral cortex, Cajal-Retzius (CR) cells settle in the preplate and coordinate the precise growth of the neocortex. Indeed, CR cells migrate tangentially from specific proliferative regions of the telencephalon (for example, the cortical hem (CH)) to populate the entire cortical surface. This is a very finely tuned process regulated by an emerging number of factors that has been sequentially revealed in recent years. However, the putative participation of one of the major families of axon guidance molecules in this process, the Semaphorins, was not explored. Here we show that Semaphorin-3E (Sema3E) is a natural negative regulator of the migration of PlexinD1-positive CR cells originating in the CH. Our results also indicate that Sema3E/PlexinD1 signalling controls the motogenic potential of CR cells in vitro and in vivo. Indeed, absence of Sema3E/PlexinD1 signalling increased the migratory properties of CR cells. This modulation implies negative effects on CXCL12/CXCR4 signalling and increased ADF/Cofilin activity.

Gil, V., Nocentini, S., del Río, J. A., (2014). Historical first descriptions of Cajal-Retzius cells: From pioneer studies to current knowledge Frontiers in Neuroanatomy 8, Article 32 (9)

Santiago Ramón y Cajal developed a great body of scientific research during the last decade of 19th century, mainly between 1888 and 1892, when he published more than 30 manuscripts. The neuronal theory, the structure of dendrites and spines, and fine microscopic descriptions of numerous neural circuits are among these studies. In addition, numerous cell types (neuronal and glial) were described by Ramón y Cajal during this time using this "reazione nera" or Golgi method. Among these neurons were the special cells of the molecular layer of the neocortex. These cells were also termed Cajal cells or Retzius cells by other colleagues. Today these cells are known as Cajal-Retzius cells. From the earliest description, several biological aspects of these fascinating cells have been analyzed (e.g., cell morphology, physiological properties, origin and cellular fate, putative function during cortical development, etc). In this review we will summarize in a temporal basis the emerging knowledge concerning this cell population with specific attention the pioneer studies of Santiago Ramón y Cajal.

Keywords: Calretinin, Cortical hem, Neocortical development, Pioneer neurons, Radial glia, Reelin

Gil, V., Del Río, J. A., (2012). Analysis of axonal growth and cell migration in 3D hydrogel cultures of embryonic mouse CNS tissue Nature Protocols 7, (2), 268-280

This protocol uses rat tail-derived type I collagen hydrogels to analyze key processes in developmental neurobiology, such as chemorepulsion and chemoattraction. The method is based on culturing small pieces of brain tissue from embryonic or early perinatal mice inside a 3D hydrogel formed by rat tail-derived type I collagen or, alternatively, by commercial Matrigel. The neural tissue is placed in the hydrogel with other brain tissue pieces or cell aggregates genetically modified to secrete a particular molecule that can generate a gradient inside the hydrogel. The present method is uncomplicated and generally reproducible, and only a few specific details need to be considered during its preparation. Moreover, the degree and behavior of axonal growth or neural migration can be observed directly using phase-contrast, fluorescence microscopy or immunocytochemical methods. This protocol can be carried out in 4 weeks.

Keywords: Cell biology, Cell culture, Developmental biology, Imaging, Model organisms, Neuroscience, Tissue culture

Llorens, Franc, Gil, Vanessa, Antonio del Rio, Jose, (2011). Emerging functions of myelin-associated proteins during development, neuronal plasticity, and neurodegeneration FASEB Journal 25, (2), 463-475

Adult mammalian central nervous system (CNS) axons have a limited regrowth capacity following injury. Myelin-associated inhibitors (MAIs) limit axonal outgrowth, and their blockage improves the regeneration of damaged fiber tracts. Three of these proteins, Nogo-A, MAG, and OMgp, share two common neuronal receptors: NgR1, together with its coreceptors [p75(NTR), TROY, and Lingo-1]; and the recently described paired immunoglobulin-like receptor B (PirB). These proteins impair neuronal regeneration by limiting axonal sprouting. Some of the elements involved in the myelin inhibitory pathways may still be unknown, but the discovery that blocking both PirB and NgR1 activities leads to near-complete release from myelin inhibition, sheds light on one of the most competitive and intense fields of neuroregeneration study in recent decades. In parallel with the identification and characterization of the roles and functions of these inhibitory molecules in axonal regeneration, data gathered in the field strongly suggest that most of these proteins have roles other than axonal growth inhibition. The discovery of a new group of interacting partners for myelin-associated receptors and ligands, as well as functional studies within or outside the CNS environment, highlights the potential new physiological roles for these proteins in processes, such as development, neuronal homeostasis, plasticity, and neurodegeneration.-Llorens, F., Gil, V., del Rio, J. A. Emerging functions of myelin-associated proteins during development, neuronal plasticity, and neurodegeneration.

Keywords: MAIs, Neural stem cells, Synapse formation

Gil, Vanessa, Bichler, Zoe, Lee, Jae K., Seira, Oscar, Llorens, Franc, Bribian, Ana, Morales, Ricardo, Claverol-Tinture, Enric, Soriano, Eduardo, Sumoy, Lauro, Zheng, Binhai, del Rio, Jose A., (2010). Developmental expression of the oligodendrocyte myelin glycoprotein in the mouse telencephalon Cerebral Cortex 20, (8), 1769-1779

The oligodendrocyte myelin glycoprotein is a glycosylphosphatidylinositol-anchored protein expressed by neurons and oligodendrocytes in the central nervous system. Attempts have been made to identify the functions of the myelin-associated inhibitory proteins (MAIPs) after axonal lesion or in neurodegeneration. However, the developmental roles of some of these proteins and their receptors remain elusive. Recent studies indicate that NgR1 and the recently discovered receptor PirB restrict cortical synaptic plasticity. However, the putative factors that trigger these effects are unknown. Because Nogo-A is mostly associated with the endoplasmic reticulum and myelin associated glycoprotein appears late during development, the putative participation of OMgp should be considered. Here, we examine the pattern of development of OMgp immunoreactive elements during mouse telencephalic development. OMgp immunoreactivity in the developing cortex follows the establishment of the thalamo-cortical barrel field. At the cellular level, we located OMgp neuronal membranes in dendrites and axons as well as in brain synaptosome fractions and axon varicosities. Lastly, the analysis of the barrel field in OMgp-deficient mice revealed that although thalamo-cortical connections were formed, their targeting in layer IV was altered, and numerous axons ectopically invaded layers II-III. Our data support the idea that early expressed MAIPs play an active role during development and point to OMgp participating in thalamo-cortical connections.

Keywords: Axon plasticity, Barrel-field specification, Cortical lamination, Myelin

Seira, O., Gavin, R., Gil, V., Llorens, F., Rangel, A., Soriano, E., del Rio, J. A., (2010). Neurites regrowth of cortical neurons by GSK3 beta inhibition independently of Nogo receptor 1 Journal of Neurochemistry 113, (6), 1644-1658

P>Lesioned axons do not regenerate in the adult mammalian CNS, owing to the over-expression of inhibitory molecules such as myelin-derived proteins or chondroitin sulphate proteoglycans. In order to overcome axon inhibition, strategies based on extrinsic and intrinsic treatments have been developed. For myelin-associated inhibition, blockage with NEP1-40, receptor bodies or IN-1 antibodies has been used. In addition, endogenous blockage of cell signalling mechanisms induced by myelin-associated proteins is a potential tool for overcoming axon inhibitory signals. We examined the participation of glycogen synthase kinase 3 beta (GSK3 beta) and extracellular-related kinase (ERK) 1/2 in axon regeneration failure in lesioned cortical neurons. We also investigated whether pharmacological blockage of GSK3 beta and ERK1/2 activities facilitates regeneration after myelin-directed inhibition in two models: (i) cerebellar granule cells and (ii) lesioned entorhino-hippocampal pathway in slice cultures, and whether the regenerative effects are mediated by Nogo Receptor 1 (NgR1). We demonstrate that, in contrast to ERK1/2 inhibition, the pharmacological treatment of GSK3 beta inhibition strongly facilitated regrowth of cerebellar granule neurons over myelin independently of NgR1. Finally, these regenerative effects were corroborated in the lesioned entorhino-hippocampal pathway in NgR1-/- mutant mice. These results provide new findings for the development of new assays and strategies to enhance axon regeneration in injured cortical connections.

Keywords: Axon inhibition, Nogo Receptor complex, Organotypic slice cultures, Pharmacological treatment

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