FGF-2 and anosmin-1 are selectively expressed in different types of multiple sclerosis lesions

Multiple sclerosis is a demyelinating disease that affects ~2,000,000 people worldwide. In the advanced stages of the disease, endogenous oligodendrocyte precursors cannot colonize the lesions or differentiate into myelinating oligodendrocytes. During development, both FGF-2 and Anosmin-1 participate in oligodendrocyte precursor cell migration, acting via the FGF receptor 1 (FGFR1). Hence, we performed a histopathological and molecular analysis of these developmental modulators in postmortem tissue blocks from multiple sclerosis patients. Accordingly, we demonstrate that the distribution of FGF-2 and Anosmin-1 varies between the different types of multiple sclerosis lesions: FGF-2 is expressed only within active lesions and in the periplaque of chronic lesions, whereas Anosmin-1 is upregulated within chronic lesions and is totally absent in active lesions. We show that the endogenous oligodendrocyte precursor cells recruited toward chronic-active lesions express FGFR1, possibly in response to the FGF-2 produced by microglial cells in the periplaque. Also in human tissue, FGF-2 is upregulated in perivascular astrocytes in regions of the normal-appearing gray matter, where the integrity of the blood-brain barrier is compromised. In culture, FGF-2 and Anosmin-1 influence adult mouse oligodendrocyte precursor cell migration in the same manner as at embryonic stages, providing an explanation for the histopathological observations: FGF-2 attracts/ enhances its migration, which is hindered by Anosmin-1. We propose that FGF-2 and Anosmin-1 are markers for the histopathological type and the level of inflammation of multiple sclerosis lesions, and that they may serve as novel pharmacogenetic targets to design future therapies that favor effective remyelination and protect the blood-brain barrier. © 2011 the authors.Peer Reviewe

Santiago Ramón y Cajal: un modelo de excelencia para desarrollar competencias en el Grado en Medicina

El presente proyecto ha acercado la figura de Santiago Ramón y Cajal a los estudiantes de Medicina como estrategia para el desarrollo de competencias generales, específicas y transversales necesarias para la formación de profesionales competentes. Se han realizado una serie de actividades en torno a nuestro Premio Nobel que han involucrado a docentes, investigadores y clínicos

Gene therapy with mesenchymal stem cells expressing IFN-ß ameliorates neuroinflammation in experimental models of multiple sclerosis

[Background and Purpose]: Recombinant IFN‐ß is one of the first‐line treatments in multiple sclerosis (MS), despite its lack of efficacy in some patients. In this context, mesenchymal stem cells (MSCs) represent a promising therapeutic alternative due to their immunomodulatory properties and multipotency. Moreover, by taking advantage of their pathotropism, these cells can be genetically modified to be used as carriers for delivering or secreting therapeutic drugs into injured tissues. Here, we report the therapeutic effect of systemic delivery of adipose‐derived MSCs (AdMSCs), transduced with the IFN‐β gene, into mice with experimental autoimmune encephalomyelitis (EAE).[Experimental Approach]: Relapsing–remitting and chronic progressive EAE were induced in mice. Cells were injected i.v. Disease severity, inflammation and tissue damage were assessed clinically, by flow cytometry of spleens and histopathological evaluation of the CNS respectively.[Key Results]: Genetic engineering did not modify the biological characteristics of these AdMSCs (morphology, growth rate, immunophenotype and multipotency). Furthermore, the transduction of IFN‐ß to AdMSCs maintained and, in some cases, enhanced the functional properties of AdMSCs by ameliorating the symptoms of MS in EAE models and by decreasing indications of peripheral and central neuro‐inflammation.[Conclusion and Implications]: Gene therapy was found to be more effective than cell therapy in ameliorating several clinical parameters in both EAE models, presumably due to the continuous expression of IFN‐β. Furthermore, it has significant advantages over AdMSC therapy, and also over systemic IFN‐ß treatment, by providing long‐term expression of the cytokine at therapeutic concentrations and reducing the frequency of injections, while minimizing dose‐limiting side effects.This work was supported by Fondo de Investigaciones Sanitarias ISCIII (Spain) and Fondo Europeo de Desarrollo Regional (FEDER) from the European Union through the research grants PI12/01097 and PI15/00963 and ISCIII Red de Terapia Celular TerCel RD12/0019/0006 to F.M., by the Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía‐FEDER/Fondo de Cohesion Europeo (FSE) de Andalucía through the research grants P09‐CTS‐04532, PI‐57069 and PAIDI‐Bio‐326 to F.M. and PI‐0160/2012 to K.B. M.J.P.‐M. has been supported by grants from Red Temática de Investigación Cooperativa Red Española de Esclerosis Múltiple REEM (RD07/0060 and RD12/0032). B.O. is financed by a contract from Excelent Project CTS‐7670/11 from Consejería de Economía, Innovación, Ciencia y Empleo (Junta de Andalucía)

Extracellular matrix protein anosmin-1 overexpression alters dopaminergic phenotype in the CNS and the PNS with no pathogenic consequences in a MPTP model of Parkinson’s disease

The development and survival of dopaminergic neurons are influenced by the fibroblast growth factor (FGF) pathway. Anosmin-1 (A1) is an extracellular matrix protein that acts as a major regulator of this signaling pathway, controlling FGF diffusion, and receptor interaction and shuttling. In particular, previous work showed that A1 overexpression results in more dopaminergic neurons in the olfactory bulb. Prompted by those intriguing results, in this study, we investigated the effects of A1 overexpression on different populations of catecholaminergic neurons in the central (CNS) and the peripheral nervous systems (PNS). We found that A1 overexpression increases the number of dopaminergic substantia nigra pars compacta (SNpc) neurons and alters the striosome/matrix organization of the striatum. Interestingly, these numerical and morphological changes in the nigrostriatal pathway of A1-mice did not confer an altered susceptibility to experimental MPTP-parkinsonism with respect to wild-type controls. Moreover, the study of the effects of A1 overexpression was extended to different dopaminergic tissues associated with the PNS, detecting a significant reduction in the number of dopaminergic chemosensitive carotid body glomus cells in A1-mice. Overall, our work shows that A1 regulates the development and survival of dopaminergic neurons in different nuclei of the mammalian nervous system.This research was supported by MCIN/Spanish Research Agency (AEI)/grants PID2019-105995RB-I00 (J.J.T.-A. and J.V.) and PID2019-109858RB-I00 (to F. dC.); ISCIII grants Red TerCel, RD16/0011/0025 (J.J.T.-A.), PI12/02574 (J.J.T.-A.), CP21/00106 (DG-G) and PI22/00156 (DG-G); Consejería de Innovación, Ciencia y Empresa grant CTS2739 (J.J.T.-A.), Consejería de Economía, Conocimiento, Empresas y Universidad grant US-1380891 (J.J.T.-A. and J.V.), Junta de Andalucía.Funding for open access publishing: Universidad de Sevilla/CBUA.Peer reviewe

Anosmin-1 over-expression increases adult neurogenesis in the subventricular zone and neuroblast migration to the olfactory bulb

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.This research was supported by grants from the Spanish Ministerio de Economía, Innovación y Competitividad MINECO (SAF2009-07842, ADE10-0010, RD07-0060-2007, RD12-0032-12 and SAF2012-40023 to FdC; and BFU2010-18284 to JMG-V), FISCAM (Gobierno de Castilla-La Mancha, Spain—Grant Number PI2007-66), the Junta de Castilla y León (Spain, to EW), and from the Fundación Eugenio Rodríguez Pascual (Spain) to FdC. DGG and VMB were PhD students hired by Gobierno de Castilla-La Mancha (MOV2010-JI/11 and MOV2007-JI/19, respectively). FdCS is a CSIC staff scientist in special permission hired by SESCAM (Gobierno de Castilla-La Mancha, Spain). PFE was a researcher hired by SESCAM (Gobierno de Castilla-La Mancha) and ADE10-0010.Peer reviewe

The Cajal School in the Peripheral Nervous System: The Transcendent Contributions of Fernando de Castro on the Microscopic Structure of Sensory and Autonomic Motor Ganglia

The fine structure of the autonomic nervous system was largely unknown at the beginning of the second decade of the 20th century. Although relatively anatomists and histologists had studied the subject, even the assays by the great Russian histologist Alexander Dogiel and the Spanish Nobel Prize laureate, Santiago Ramón y Cajal, were incomplete. In a time which witnessed fundamental discoveries by Langley, Loewi and Dale on the physiology of the autonomic nervous system, both reputed researchers entrusted one of their outstanding disciples to the challenge to further investigate autonomic structures: the Russian B.I. Lawrentjew and the Spanish Fernando de Castro developed new technical approaches with spectacular results. In the mid of the 1920’s, both young neuroscientists were worldwide recognized as the top experts in the field. In the present work we describe the main discoveries by Fernando de Castro in those years regarding the structure of sympathetic and sensory ganglia, the organization of the synaptic contacts in these ganglia, and the nature of their innervation, later materialized in their respective chapters, personally invited by the editor, in Wilder Penfield’s famous textbook on Neurology and the Nervous System. Most of these discoveries remain fully alive today.The work of our group is supported with grants from the following Spanish institutions: ministerio de Economía y Competitividad-MINECO (SAF2012-40023, RD12-0032-12 [partially cofinanced by FEDER “Una manera de hacer Europa”]), Fundación Eugenio Rodríguez Pascual, all to FdC.Peer reviewedPeer Reviewe

Remielinización en esclerosis múltiple: (casi) posible y, desde luego, necesaria

Ponencia presentada en el "Proyecto Emerald. Avances en esclerosis múltiple" celebrado el 3 de junio de 2022 en el Hotel NH Eurobuilding, Madrid.Janssen Neuroscienc

Editorial: The Major Discoveries of Cajal and His Disciples: Consolidated Milestones for the Neuroscience of the XXIst Century

Our current research activities are financed with grants from the Spanish Ministerio de Economía y Competitividad-MINECO (SAF2012-40023, RD12-0032-12) and CSIC (2015201023) to FC.Peer reviewedPeer Reviewe

Protocortex versus protomap: a perspective from the olfactory bulb

[EN]Introduction and aim. The olfactory sensory system is a unique model for the research of guidance and connectivity of growing axons. During development, the olfactory epithelium, the olfactory bulb and the olfactory cortex differentiate several cell types and extend projection axons. Because there is a close relationship between these three structures, we ask the question as to whether establishment of the olfactory bulb central projections can proceed independently of the arrival of the olfactory sensory afferents. This raises another more general question: is establishment of afferent connections necessary to awake a developmental program in target cells? Development. The initial establishment of the olfactory bulb central projections occurs independently of the arrival of the olfactory axons from the olfactory epithelium, which reinforces the idea that cortical regions are already patterned before migration of newborn neurons, at least for the olfactory bulb and maybe for the entire brain. This implies a strict intrinsic molecular control of the distinct olfactory structures, independent one of each other. Conclusions. How then, do axonal projections find their correct way within the brain? Contact-mediated mechanisms and chemotropic molecules cooperate to fix their position in the telencephalon, prevent bulbar axons from invading structures other than the olfactory cortex and, at the same time, stimulate axonal branching in an orchestra of both, attractive/promoting and repulsive/inhibiting signals. At later stages, the mature appearance of the olfactory bulb will be completed and refined.[ES]El sistema olfativo es un modelo extraordinario para la investigación de la guía y la conectividad del crecimiento axonal. Durante el desarrollo, el epitelio olfativo, el bulbo olfativo y la corteza olfativa diferencian varios tipos celulares, y extienden sus proyecciones axonales. Dado que hay una relación estrecha entre estas tres estructuras, nos hacemos la siguiente pregunta: ¿es necesaria la llegada de las aferencias sensoriales procedentes del epitelio olfativo para iniciarse la formación de las proyecciones centrales del bulbo olfativo? Esto nos lleva a otra pregunta más general: ¿es necesario el establecimiento de conexiones aferentes para inducirse un programa de desarrollo en las células diana? Desarrollo. El establecimiento inicial de las proyecciones centrales del bulbo olfativo ocurre independientemente de la llegada de los axones del epitelio olfativo, lo que refuerza la idea de que las diferentes regiones corticales se predeterminan ya antes de la migración de neuronas posmitóticas, por lo menos en el caso del bulbo olfativo. Esto implica un control molecular, intrínseco y estricto de las distintas estructuras del sistema olfativo. Conclusiones. Entonces, ¿cómo encuentran las proyecciones axonales su correcta localización dentro del cerebro? Mecanismos por contacto y moléculas quimiotrópicas cooperan para fijar su posición en el telencéfalo, y evitan que los axones del bulbo invadan otras estructuras diferentes a la corteza olfativa. Al mismo tiempo, estimulan la formación de colaterales axónicas, en una orquesta de señales atrayentes/permisivas y repulsivas/inhibidoras. En etapas posteriores del desarrollo, se completará la apariencia madura del bulbo olfativoProyecto de LLM: BFI 2003-00139 (MCYT). Proyectos de F de C: PI020768 (FIS, Ministerio de Sanidad), SA053/04 (Junta de Castilla y León) y Fundació la Caixa.Peer reviewe

Vida y obra del neurocientífico Oleksandr Chernyajivsky (1869-1939), el discípulo ucraniano de Cajal

Conferencia oral invitada al Seminario de la revista ¿Neurosciences and History