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1.
Glia ; 71(1): 91-102, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-35411970

RESUMEN

In the central nervous system, oligodendrocytes synthesize the myelin, a specialized membrane to wrap axons in a discontinuous way allowing a rapid saltatory nerve impulse conduction. Oligodendrocytes express a number of growth factors and neurotransmitters receptors that allow them to sense the environment and interact with neurons and other glial cells. Depending on the cell cycle stage, oligodendrocytes may respond to these signals by regulating their survival, proliferation, migration, and differentiation. Among these signals are the endocannabinoids, lipidic molecules synthesized from phospholipids in the plasma membrane in response to cell activation. Here, we discuss the evidence showing that oligodendrocytes express a full endocannabinoid signaling machinery involved in physiological oligodendrocyte functions that can be therapeutically exploited to promote remyelination in central nervous system pathologies.


Asunto(s)
Endocannabinoides , Oligodendroglía , Endocannabinoides/metabolismo , Oligodendroglía/metabolismo , Vaina de Mielina/metabolismo , Axones/metabolismo , Sistema Nervioso Central/metabolismo , Diferenciación Celular/fisiología
2.
J Neurochem ; 158(3): 640-656, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-33942314

RESUMEN

CB1 cannabinoid receptor is widely expressed in the central nervous system of animals from late prenatal development to adulthood. Appropriate activation and signaling of CB1 cannabinoid receptors in cortical interneurons are crucial during perinatal/postnatal ages and adolescence, when long-lasting changes in brain activity may elicit subsequent appearance of disorders in the adult brain. Here we used an optimized immunoprecipitation protocol based on specific antibodies followed by shot-gun proteomics to find CB1 interacting partners in postnatal rat GABAergic cortical neurons in vitro at two different stages of maturation. Besides describing new proteins associated with CB1 like dihydrolipoyllysine-residue acetyltransferase component of pyruvate dehydrogenase complex (DLAT), fatty acid synthase (FASN), tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ), voltage-dependent anion channel 1 (VDAC1), myosin phosphatase Rho-interacting protein (MPRIP) or usher syndrome type-1C protein-binding protein 1 (USHBP1), we show that the signaling complex of CB1 is different between maturational stages. Interestingly, the CB1 signaling complex is enriched at the more immature stage in mitochondrial associated proteins and metabolic molecular functions, whereas at more mature stage, CB1 complex is increased in maturation and synaptic-associated proteins. We describe also interacting partners specifically immunoprecipitated with either N-terminal or C-terminal CB1 directed antibodies. Our results highlight new players that may be affected by altered cannabinoid signaling at this critical window of postnatal cortical development.


Asunto(s)
Corteza Cerebral/embriología , Corteza Cerebral/metabolismo , Neuronas GABAérgicas/fisiología , Receptor Cannabinoide CB1/genética , Receptor Cannabinoide CB1/metabolismo , Animales , Células Cultivadas , Femenino , Embarazo , Ratas , Ratas Wistar , Transducción de Señal/fisiología
3.
Glia ; 62(3): 374-86, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24375670

RESUMEN

Signaling through fibroblast growth factor receptors (FGFRs) is essential for many cellular processes including proliferation and migration, as well as differentiation events such as myelination. Anosmin-1 is an extracellular matrix (ECM) glycoprotein that interacts with the fibroblast growth factor receptor 1 (FGFR1) to exert its biological actions through this receptor, although the intracellular pathways underlying anosmin-1 signaling remain largely unknown. This protein is defective in the X-linked form of Kallmann syndrome (KS) and has a prominent role in the migration of neuronal and oligodendroglial precursors. We have shown that anosmin-1 exerts a chemotactic effect via FGFR1 on neuronal precursors from the subventricular zone (SVZ) and the essential role of the ERK1/2 signaling. We report here the positive chemotactic effect of FGF2 and anosmin-1 on rat and mouse postnatal OPCs via FGFR1. The same effect was observed with the truncated N-terminal region of anosmin-1 (A1Nt). The introduction in anosmin-1 of the missense mutation F517L found in patients suffering from KS annulled the chemotactic activity; however, the mutant form carrying the disease-causing mutation E514K also found in KS patients, behaved as the wild-type protein. The chemoattraction exhibited by FGF2 and anosmin-1 on OPCs was blocked by the mitogen-activated protein kinase (MAPK) inhibitor U0126, suggesting that the activation of the ERK1/2 MAPK signaling pathway following interaction with the FGFR1 is necessary for FGF2 and anosmin-1 to exert their chemotactic effect. In fact, both proteins were able to induce the phosphorylation of the ERK1/2 kinases after the activation of the FGFR1 receptor.


Asunto(s)
Quimiotaxis/fisiología , Proteínas de la Matriz Extracelular/metabolismo , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Sistema de Señalización de MAP Quinasas/fisiología , Proteínas del Tejido Nervioso/metabolismo , Oligodendroglía/fisiología , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/fisiología , Células Madre/fisiología , Animales , Animales Recién Nacidos , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Células Cultivadas , Quimiotaxis/efectos de los fármacos , Cricetulus , Inhibidores Enzimáticos/farmacología , Proteínas de la Matriz Extracelular/genética , Factor 2 de Crecimiento de Fibroblastos/genética , Gangliósidos/metabolismo , Humanos , Ventrículos Laterales/citología , Sistema de Señalización de MAP Quinasas/genética , Ratones , Ratones Endogámicos C57BL , Mutación/genética , Proteínas del Tejido Nervioso/genética , Factor de Transcripción 2 de los Oligodendrocitos , Oligodendroglía/efectos de los fármacos , Ratas , Ratas Wistar , Células Madre/efectos de los fármacos , Factores de Tiempo
4.
J Neurochem ; 124(5): 708-20, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23189990

RESUMEN

The protein anosmin-1, coded by the KAL1 gene responsible for the X-linked form of Kallmann syndrome (KS), exerts its biological effects mainly through the interaction with and signal modulation of fibroblast growth factor receptor 1 (FGFR1). We have previously shown the interaction of the third fibronectin-like type 3 (FnIII) domain and the N-terminal region of anosmin-1 with FGFR1. Here, we demonstrate that missense mutations reported in patients with KS, C172R and N267K did not alter or substantially reduce, respectively, the binding to FGFR1. These substitutions annulled the chemoattraction of the full-length protein over subventricular zone (SVZ) neuronal precursors (NPs), but they did not annul it in the N-terminal-truncated protein (A1Nt). We also show that although not essential for binding to FGFR1, the cysteine-rich (CR) region is necessary for anosmin-1 function and that FnIII.3 cannot substitute for FnIII.1 function. Truncated proteins recapitulating nonsense mutations found in KS patients did not show the chemotropic effect on SVZ NPs, suggesting that the presence behind FnIII.1 of any part of anosmin-1 produces an unstable protein incapable of action. We also identify the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway as necessary for the chemotropic effect exerted by FGF2 and anosmin-1 on rat SVZ NPs.


Asunto(s)
Proteínas de la Matriz Extracelular/química , Proteínas de la Matriz Extracelular/metabolismo , Síndrome de Kallmann/metabolismo , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/metabolismo , Células-Madre Neurales/metabolismo , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismo , Secuencias de Aminoácidos , Animales , Proteínas de la Matriz Extracelular/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Síndrome de Kallmann/genética , Sistema de Señalización de MAP Quinasas/fisiología , Proteínas de la Leche/química , Proteínas del Tejido Nervioso/genética , Ratas , Ratas Wistar , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/química
5.
Cell Signal ; 98: 110417, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-35878754

RESUMEN

The X-linked form of Kallmann syndrome (KS), characterized by hypogonadotropic hypogonadism and anosmia, is due to mutations in the ANOS1 gene that encodes for the extracellular matrix (ECM) protein anosmin 1. Prokineticins (PKs) exert their biological functions through the activation of the G protein-coupled receptors (GPCRs) prokineticin receptor 1 and 2 (PKR1, 2), and mutations in the PK2 and PKR2 genes are involved in the pathogenesis of KS. We have previously shown interaction between PKR2 and anosmin 1 in vitro. In the current report we present evidence of the modulation of PK2/PKR2 activity by anosmin 1, since this protein is able to enhance the activation of the ERK1/2 (extracellular signal-regulated kinase 1/2) pathway elicited by PK2 through PKR2. We also show that the N-terminal region of anosmin 1, capable of binding to the PK2-binding domain of PKR2, seems to be responsible for this effect. The whey acidic protein domain (WAP) is necessary for this modulatory activity, although data from GST pull-down (glutathione-S-transferase) and analysis of the N267K mutation in the fibronectin type III domain 1 (FnIII.1) suggest the cysteine-rich (CR) and the FnIII.1 domains could assist the WAP domain both in the binding to PKR2 and in the modulation of the activation of the receptor by PK2. Our data support the idea of a modulatory role of anosmin 1 in the biological effects controlled by the PK2/PKR2 system.


Asunto(s)
Síndrome de Kallmann , Proteínas del Tejido Nervioso , Proteínas de la Matriz Extracelular/metabolismo , Humanos , Síndrome de Kallmann/genética , Síndrome de Kallmann/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo
6.
Cells ; 11(8)2022 04 09.
Artículo en Inglés | MEDLINE | ID: mdl-35455962

RESUMEN

The risk of complications following surgical procedures is significantly increased in patients with SARS-CoV-2 infection. However, the mechanisms underlying these correlations are not fully known. Spinal cord injury (SCI) patients who underwent reconstructive surgery for pressure ulcers (PUs) before and during the COVID-19 pandemic were included in this study. The patient's postoperative progression was registered, and the subcutaneous white adipose tissue (s-WAT) surrounding the ulcers was analyzed by proteomic and immunohistochemical assays to identify the molecular/cellular signatures of impaired recovery. Patients with SCI and a COVID-19-positive diagnosis showed worse recovery and severe postoperative complications, requiring reintervention. Several proteins were upregulated in the adipose tissue of these patients. Among them, CKMT2 and CKM stood out, and CKM increased for up to 60 days after the COVID-19 diagnosis. Moreover, CKMT2 and CKM were largely found in MGCs within the s-WAT of COVID patients. Some of these proteins presented post-translational modifications and were targeted by autoantibodies in the serum of COVID patients. Overall, our results indicate that CKMT2, CKM, and the presence of MGCs in the adipose tissue surrounding PUs in post-COVID patients could be predictive biomarkers of postsurgical complications. These results suggest that the inflammatory response in adipose tissue may underlie the defective repair seen after surgery.


Asunto(s)
COVID-19 , Úlcera por Presión , Traumatismos de la Médula Espinal , Tejido Adiposo/metabolismo , COVID-19/complicaciones , Prueba de COVID-19 , Creatina Quinasa/metabolismo , Forma Mitocondrial de la Creatina-Quinasa/metabolismo , Humanos , Pandemias , Úlcera por Presión/epidemiología , Úlcera por Presión/etiología , Úlcera por Presión/cirugía , Proteómica , SARS-CoV-2 , Traumatismos de la Médula Espinal/complicaciones , Traumatismos de la Médula Espinal/cirugía , Supuración/complicaciones , Regulación hacia Arriba
7.
J Cell Biol ; 173(2): 291-9, 2006 Apr 24.
Artículo en Inglés | MEDLINE | ID: mdl-16636148

RESUMEN

Neurotrophins play an essential role in mammalian development. Most of their functions have been attributed to activation of the kinase-active Trk receptors and the p75 neurotrophin receptor. Truncated Trk receptor isoforms lacking the kinase domain are abundantly expressed during development and in the adult; however, their function and signaling capacity is largely unknown. We show that the neurotrophin-3 (NT3) TrkCT1-truncated receptor binds to the scaffold protein tamalin in a ligand-dependent manner. Moreover, NT3 initiation of this complex leads to activation of the Rac1 GTPase through adenosine diphosphate-ribosylation factor 6 (Arf6). At the cellular level, NT3 binding to TrkCT1-tamalin induces Arf6 translocation to the membrane, which in turn causes membrane ruffling and the formation of cellular protrusions. Thus, our data identify a new signaling pathway elicited by the kinase-deficient TrkCT1 receptor. Moreover, we establish NT3 as an upstream regulator of Arf6.


Asunto(s)
Factores de Ribosilacion-ADP/metabolismo , Proteínas Portadoras/metabolismo , Proteínas de la Membrana/metabolismo , Receptor trkC/fisiología , Transducción de Señal , Proteína de Unión al GTP rac1/metabolismo , Factor 6 de Ribosilación del ADP , Línea Celular , Células Cultivadas , Humanos , Modelos Biológicos , Isoformas de Proteínas/fisiología
8.
J Neurochem ; 115(5): 1256-65, 2010 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-20874775

RESUMEN

Anosmin-1, defective in Kallmann's syndrome, participates in the adhesion, migration and differentiation of different cell types in the CNS. Although not fully understood, the mechanisms of action of Anosmin-1 involve the interaction with different proteins, being the interaction with fibroblast growth factor receptor 1 (FGFR1) and the modulation of its signalling the best studied to date. Using glutathione-S-transferase pull-down assays we demonstrate that the FnIII.3 (Fibronectin-like type III) domain and the combination whey acidic protein-FnIII.1, but not each of them individually, interact with FGFR1. The interaction of the whey acidic protein-FnIII.1 domains is substantially reduced when the cysteine-rich region is present, suggesting a likely regulatory role for this domain. The introduction in FnIII.3 of any of the two missense mutations found in Kallmann's syndrome patients, E514K and F517L, abolished the interaction with FGFR1, what suggests an important role for these residues in the interaction. Interestingly, the chemoattraction of Anosmin-1 on rat neuronal precursors (NPs) via FGFR1 is retained by the N-terminal region of Anosmin-1 but not by FnIII.3 alone, and is lost in proteins carrying either one of the missense mutations, probably because of a highly reduced binding capacity to FGFR1. We also describe homophilic interaction Anosmin-1/Anosmin-1 via the FnIII repeats 1 and 4, and the interaction of FnIII.1 and FnIII.3 with Fibronectin and of FnIII.3 with Laminin.


Asunto(s)
Proteínas de la Matriz Extracelular/química , Proteínas de la Matriz Extracelular/fisiología , Matriz Extracelular/química , Matriz Extracelular/metabolismo , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/fisiología , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismo , Animales , Animales Recién Nacidos , Células CHO , Ventriculitis Cerebral , Quimiotaxis/genética , Quimiotaxis/fisiología , Cricetinae , Cricetulus , Medios de Cultivo Condicionados/farmacología , Cisteína/genética , Cisteína/metabolismo , Inhibidores Enzimáticos/farmacología , Proteínas de la Matriz Extracelular/genética , Fibronectinas/genética , Fibronectinas/metabolismo , Humanos , Inmunoprecipitación/métodos , Laminina , Mutación/genética , Proteínas del Tejido Nervioso/genética , Células-Madre Neurales/efectos de los fármacos , Células-Madre Neurales/fisiología , Estructura Terciaria de Proteína/fisiología , Pirroles/farmacología , Ratas , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Transfección/métodos
9.
J Neurosci Methods ; 337: 108680, 2020 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-32145227

RESUMEN

BACKGROUND: Cannabinoid receptor 1 (CB1) identification by western blot (WB) has generated a great deal of controversial data making the interpretation of the results difficult. Our purpose is to find the most adequate experimental conditions to detect CB1 by WB and immunoprecipitation (IP) as a first step towards the study of CB1 interactome. NEW METHOD: We use CB1 knockout mice tissue as negative controls and describe appropriate sample handling conditions for CB1 detection by WB and IP from brain and cortical neuron cultures. RESULTS: Sample heating above 65 °C greatly impaired CB1 detection by WB, since it favored the formation of high molecular weight aggregates. We also show the convenience of using n-dodecyl-ß-d-maltoside (DDM) as a detergent for the detection of CB1 by WB and, mostly, for IP. COMPARISON WITH EXISTING METHOD(S): We obtain consistent and specific CB1 detection by WB and IP using four different commercial antibodies and KO tissue for an accurate CB1 identification. We clarify the identification of the receptor in complex samples compared with the diverse and unclear results obtained using standard WB methods. CONCLUSIONS: We establish experimental guidelines for the detection of CB1 by WB and the study of CB1 interacting proteins by IP. We propose a new interpretation of CB1 WB and IP data based on the folding and packing state of the protein and the detergent used. The standardization of the most advantageous conditions for coimmunoprecipitation (CoIP) would be a useful tool for the future study of the interactome of CB1.


Asunto(s)
Encéfalo , Ingestión de Alimentos , Animales , Western Blotting , Ratones , Ratones Noqueados , Receptor Cannabinoide CB1/genética , Receptor Cannabinoide CB2 , Receptores de Cannabinoides/genética
10.
J Clin Med ; 9(6)2020 Jun 02.
Artículo en Inglés | MEDLINE | ID: mdl-32498223

RESUMEN

Besides giving rise to oligodendrocytes (the only myelin-forming cell in the Central Nervous System (CNS) in physiological conditions), Oligodendrocyte Precursor Cells (OPCs) are responsible for spontaneous remyelination after a demyelinating lesion. They are present along the mouse and human CNS, both during development and in adulthood, yet how OPC physiological behavior is modified throughout life is not fully understood. The activity of adult human OPCs is still particularly unexplored. Significantly, most of the molecules involved in OPC-mediated remyelination are also involved in their development, a phenomenon that may be clinically relevant. In the present article, we have compared the intrinsic properties of OPCs isolated from the cerebral cortex of neonatal, postnatal and adult mice, as well as those recovered from neurosurgical adult human cerebral cortex tissue. By analyzing intact OPCs for the first time with 1H High Resolution Magic Angle Spinning Nuclear Magnetic Resonance (1H HR-MAS NMR) spectroscopy, we show that these cells behave distinctly and that they have different metabolic patterns in function for their stage of maturity. Moreover, their response to Fibroblast Growth Gactor-2 (FGF-2) and anosmin-1 (two molecules that have known effects on OPC biology during development and that are overexpressed in individuals with Multiple Sclerosis (MS)) differs in relation to their developmental stage and in the function of the species. Our data reveal that the behavior of adult human and mouse OPCs differs in a very dynamic way that should be very relevant when testing drugs and for the proper design of effective pharmacological and/or cell therapies for MS.

11.
Mol Cell Biol ; 26(14): 5249-58, 2006 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-16809763

RESUMEN

Trafficking and cell adhesion are key properties of cells of the immune system. However, the molecular pathways that control these cellular behaviors are still poorly understood. Cybr is a scaffold protein highly expressed in the hematopoietic/immune system whose physiological role is still unknown. In vitro studies have shown it regulates LFA-1, a crucial molecule in lymphocyte attachment and migration. Cybr also binds cytohesin-1, a guanine nucleotide exchange factor for the ARF GTPases, which affects actin cytoskeleton remodeling during cell migration. Here we show that expression of Cybr in vivo is differentially modulated by type 1 cytokines during lymphocyte maturation. In mice, Cybr deficiency negatively affects leukocytes circulating in blood and lymphocytes present in the lymph nodes. Moreover, in a Th1-polarized mouse model, lymphocyte trafficking is impaired by loss of Cybr, and Cybr-deficient mice with aseptic peritonitis have fewer cells than controls present in the peritoneal cavity, as well as fewer leukocytes leaving the bloodstream. Mutant mice injected with Moloney murine sarcoma/leukemia virus develop significantly larger tumors than wild-type mice and have reduced lymph node enlargement, suggesting reduced cytotoxic T-lymphocyte migration. Taken together, these data support a role for Cybr in leukocyte trafficking, especially in response to proinflammatory cytokines in stress conditions.


Asunto(s)
Citocinas/fisiología , Proteínas del Citoesqueleto/fisiología , Leucocitos/fisiología , Animales , Diferenciación Celular , Movimiento Celular , Proteínas del Citoesqueleto/deficiencia , Proteínas del Citoesqueleto/genética , Expresión Génica , Leucocitos/citología , Leucocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Virus del Sarcoma Murino de Moloney , Peritonitis/inmunología , Peritonitis/patología , Infecciones por Retroviridae/inmunología , Infecciones por Retroviridae/patología , Sarcoma Experimental/inmunología , Sarcoma Experimental/patología , Linfocitos T/citología , Linfocitos T/inmunología , Linfocitos T/fisiología , Infecciones Tumorales por Virus/inmunología , Infecciones Tumorales por Virus/patología
12.
Methods Enzymol ; 438: 171-83, 2008.
Artículo en Inglés | MEDLINE | ID: mdl-18413248

RESUMEN

Arf GTP-binding proteins and Rho-family GTPases play key roles in regulating membrane remodeling and cytoskeletal reorganization involved in cell movement. Several studies have implicated neurotrophins and their receptors as upstream activators of these small GTP-binding proteins, however, the mechanisms and the cell type specificity of this neurotrophin activity are still under investigation. Here we describe the rationale and protocols used for the dissection of an NT3 activated pathway that leads to the specific activation of Arf6 and Rac1.


Asunto(s)
Factores de Ribosilacion-ADP/metabolismo , Neuronas/metabolismo , Neurotrofina 3/fisiología , Proteína de Unión al GTP rac1/metabolismo , Factor 6 de Ribosilación del ADP , Animales , Línea Celular , Activación Enzimática , Humanos , Ratones , Ratones Mutantes
13.
Biochem Pharmacol ; 157: 180-188, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30195734

RESUMEN

While the endocannabinoid 2-arachidonoylglycerol (2-AG) is thought to enhance the proliferation and differentiation of oligodendrocyte progenitor cells (OPCs) in vitro, less is known about how endogenous 2-AG may influence the migration of these cells. When we assessed this in Agarose drop and Boyden chemotaxis chamber assays, inhibiting the sn-1-diacylglycerol lipases α and ß (DAGLs) that are responsible for 2-AG synthesis significantly reduced the migration of OPCs stimulated by platelet-derived growth factor-AA (PDGF) and basic fibroblast growth factor (FGF). Likewise, antagonists of the CB1 and CB2 cannabinoid receptors (AM281 and AM630, respectively) produced a similar inhibition of OPC migration. By contrast, increasing the levels of endogenous 2-AG by blocking its degradation (impairing monoacylglycerol lipase activity with JZL-184) significantly increased OPC migration, as did agonists of the CB1, CB2 or CB1/CB2 cannabinoid receptors. This latter effect was abolished by selective CB1 or CB2 antagonists, strongly suggesting that cannabinoid receptor activation specifically potentiates OPC chemotaxis and chemokinesis in response to PDGF/FGF. Furthermore, the chemoattractive activity of these cannabinoid receptor agonists on OPCs was even evident in the absence of PDGF/FGF. In cultured brain slices prepared from the corpus callosum of postnatal rat brains, DAGL or cannabinoid receptor inhibition substantially diminished the in situ migration of Sox10+ OPCs. Overall, these results reveal a novel function of endogenous 2-AG in PDGF and FGF induced OPC migration, highlighting the importance of the endocannabinoid system in regulating essential steps in oligodendrocyte development.


Asunto(s)
Ácidos Araquidónicos/fisiología , Movimiento Celular , Endocannabinoides/fisiología , Glicéridos/fisiología , Oligodendroglía/fisiología , Células Madre/fisiología , Animales , Ácidos Araquidónicos/antagonistas & inhibidores , Ácidos Araquidónicos/biosíntesis , Ácidos Araquidónicos/metabolismo , Agonistas de Receptores de Cannabinoides/farmacología , Antagonistas de Receptores de Cannabinoides/farmacología , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Cuerpo Calloso/citología , Endocannabinoides/antagonistas & inhibidores , Endocannabinoides/biosíntesis , Endocannabinoides/metabolismo , Glicéridos/antagonistas & inhibidores , Glicéridos/biosíntesis , Glicéridos/metabolismo , Ratas Wistar
15.
Protein Pept Lett ; 23(7): 650-5, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27184500

RESUMEN

Sexual maturation and olfactory bulb defects found in prokineticin 2 (Pk2) and prokineticin receptor 2 (Pkr2) mutant mice resembling the phenotypic characteristics of Kallmann syndrome (KS), gave rise to the question of whether these genes would have a role in KS pathogenesis. Later, mutations in both genes were identified in patients suffering from KS. The gene responsible for the Xlinked form of KS, ANOS1, encodes the ECM protein anosmin 1. Among other functions, anosmin 1 can regulate the activity of FGFR1, encoded by one of the genes involved in the autosomal transmission of KS. Therefore, it has been proposed that anosmin 1 could interact with PKR2 to modulate its activity. We present the first evidence supporting this hypothesis and report the interaction of full-length anosmin 1 with three extracellular domains of PKR2. A truncated anosmin 1 protein comprising the first three domains of the protein interacts with the second extracellular loop of PKR2, involved in PK2 binding. Finally, last three FnIII repeats of anosmin 1 also interacted with the PKR2 domains that interacted with full-length anosmin 1. Our data represent a molecular link between two of the genes involved in KS pathogenesis.


Asunto(s)
Proteínas de la Matriz Extracelular/metabolismo , Síndrome de Kallmann/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animales , Células CHO , Clonación Molecular , Cricetulus , Proteínas de la Matriz Extracelular/química , Proteínas de la Matriz Extracelular/genética , Síndrome de Kallmann/genética , Síndrome de Kallmann/patología , Ratones , Ratones Endogámicos C57BL , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/genética , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Mapas de Interacción de Proteínas , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/genética
16.
Brain Struct Funct ; 221(3): 1365-85, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25662897

RESUMEN

During development of the central nervous system, anosmin-1 (A1) works as a chemotropic cue contributing to axonal outgrowth and collateralization, as well as modulating the migration of different cell types, fibroblast growth factor receptor 1 (FGFR1) being the main receptor involved in all these events. To further understand the role of A1 during development, we have analysed the over-expression of human A1 in a transgenic mouse line. Compared with control mice during development and in early adulthood, A1 over-expressing transgenic mice showed an enhanced oligodendrocyte precursor cell (OPC) proliferation and a higher number of OPCs in the subventricular zone and in the corpus callosum (CC). The migratory capacity of OPCs from the transgenic mice is increased in vitro due to a higher basal activation of ERK1/2 mediated through FGFR1 and they also produced more myelin basic protein (MBP). In vivo, the over-expression of A1 resulted in an elevated number of mature oligodendrocytes with higher levels of MBP mRNA and protein, as well as increased levels of activation of the ERK1/2 proteins, while electron microscopy revealed thicker myelin sheaths around the axons of the CC in adulthood. Also in the mature CC, the nodes of Ranvier were significantly longer and the conduction velocity of the nerve impulse in vivo was significantly increased in the CC of A1 over-expressing transgenic mice. Altogether, these data confirmed the involvement of A1 in oligodendrogliogenesis and its relevance for myelination.


Asunto(s)
Encéfalo/embriología , Encéfalo/fisiología , Movimiento Celular , Proliferación Celular , Proteínas de la Matriz Extracelular/fisiología , Vaina de Mielina/fisiología , Proteínas del Tejido Nervioso/fisiología , Oligodendroglía/fisiología , Animales , Encéfalo/metabolismo , Células Cultivadas , Cuerpo Calloso/embriología , Cuerpo Calloso/metabolismo , Cuerpo Calloso/fisiología , Cuerpo Calloso/ultraestructura , Proteínas de la Matriz Extracelular/metabolismo , Humanos , Sistema de Señalización de MAP Quinasas , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas del Tejido Nervioso/metabolismo , Oligodendroglía/metabolismo , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismo
17.
Brain Struct Funct ; 221(1): 239-60, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25300351

RESUMEN

New subventricular zone (SVZ)-derived neuroblasts that migrate via the rostral migratory stream are continuously added to the olfactory bulb (OB) of the adult rodent brain. Anosmin-1 (A1) is an extracellular matrix protein that binds to FGF receptor 1 (FGFR1) to exert its biological effects. When mutated as in Kallmann syndrome patients, A1 is associated with severe OB morphogenesis defects leading to anosmia and hypogonadotropic hypogonadism. Here, we show that A1 over-expression in adult mice strongly increases proliferation in the SVZ, mainly with symmetrical divisions, and produces substantial morphological changes in the normal SVZ architecture, where we also report the presence of FGFR1 in almost all SVZ cells. Interestingly, for the first time we show FGFR1 expression in the basal body of primary cilia in neural progenitor cells. Additionally, we have found that A1 over-expression also enhances neuroblast motility, mainly through FGFR1 activity. Together, these changes lead to a selective increase in several GABAergic interneuron populations in different OB layers. These specific alterations in the OB would be sufficient to disrupt the normal processing of sensory information and consequently alter olfactory memory. In summary, this work shows that FGFR1-mediated A1 activity plays a crucial role in the continuous remodelling of the adult OB.


Asunto(s)
Proteínas de la Matriz Extracelular/metabolismo , Proteínas de la Matriz Extracelular/fisiología , Ventrículos Laterales/fisiología , Proteínas del Tejido Nervioso/metabolismo , Proteínas del Tejido Nervioso/fisiología , Neurogénesis , Bulbo Olfatorio/fisiología , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismo , Animales , División Celular , Movimiento Celular , Células Cultivadas , Proteínas de la Matriz Extracelular/genética , Humanos , Interneuronas/metabolismo , Interneuronas/fisiología , Ventrículos Laterales/metabolismo , Ventrículos Laterales/ultraestructura , Memoria a Corto Plazo/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas del Tejido Nervioso/genética , Vías Nerviosas/metabolismo , Vías Nerviosas/fisiología , Vías Nerviosas/ultraestructura , Odorantes , Bulbo Olfatorio/metabolismo , Percepción Olfatoria/fisiología
18.
Adv Neurobiol ; 8: 273-92, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25300141

RESUMEN

Anosmin-1 is the glycoprotein encoded by the KAL1 gene and part of the extracellular matrix, which was first identified as defective in human Kallmann syndrome (KS, characterised by hypogonadotropic hypogonadism and anosmia); biochemically it is a cell adhesion protein. The meticulous biochemical dissection of the anosmin-1 domains has identified which domains are necessary for the protein to bind its different partners to display its biological effects. Research in the last decade has unravelled different roles of anosmin-1 during CNS development (axon pathfinding, axonal collateralisation, cell motility and migration), some of them intimately related with the cited KS but not only with this. More recently, anosmin-1 has been identified in other pathological scenarios both within (multiple sclerosis) and outside (cancer, atopic dermatitis) the CNS.


Asunto(s)
Proteínas de la Matriz Extracelular/genética , Síndrome de Kallmann/genética , Síndrome de Kallmann/metabolismo , Proteínas del Tejido Nervioso/genética , Neurología , Animales , Sistema Nervioso Central/crecimiento & desarrollo , Sistema Nervioso Central/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Humanos , Proteínas del Tejido Nervioso/metabolismo
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