Cux1 and Cux2 selectively target basal and apical dendritic compartments of layer II-III cortical neurons

© 2014 Wiley Periodicals, Inc. A number of recent reports implicate the differential regulation of apical and basal dendrites in autism disorders and in the higher functions of the human brain. They show that apical and basal dendrites are functionally specialized and that mechanisms regulating their development have important consequences for neuron function. The molecular identity of layer II-III neurons of the cerebral cortex is determined by the overlapping expression of Cux1 and Cux2. We previously showed that both Cux1 and Cux2 are necessary and nonredundant for normal dendrite development of layer II-III neurons. Loss of function of either gene reduced dendrite arbors, while overexpression increased dendritic complexity and suggested additive functions. We herein characterize the function of Cux1 and Cux2 in the development of apical and basal dendrites. By in vivo loss and gain of function analysis, we show that while the expression level of either Cux1 or Cux2 influences both apical and basal dendrites, they have distinct effects. Changes in Cux1 result in a marked effect on the development of the basal compartment whereas modulation of Cux2 has a stronger influence on the apical compartment. These distinct effects of Cux genes might account for the functional diversification of layer II-III neurons into different subpopulations, possibly with distinct connectivity patterns and modes of neuron response. Our data suggest that by their differential effects on basal and apical dendrites, Cux1 and Cux2 can promote the integration of layer II-III neurons in the intracortical networks in highly specific ways.Peer Reviewe

Salud mental y sistema penitenciario

La naturaleza y la percepción de la salud mental ha variado a lo largo de la historia y ha tenido una influencia distinta en las diferentes comunidades. Su atención como parte de la sanidad en general es relativamente reciente. La influencia de esta materia en el ámbito penal y penitenciario se ha visto reflejado en numerosos textos legales y convenios internacionales, pero su mayor desarrollo procede esencialmente de las Instrucciones de la Secretaría General de Instituciones Penitenciarias. El elemento regimental por el que la actividad de los establecimientos penitenciarios se ve influida se complementa con unas necesidades asistenciales y resocializadoras que no pueden ser soslayadas. En este sentido, se han articulado mecanismos para el tratamiento de la salud mental en la población penitenciaria en general y en particular a aquella que padece enfermedades mentales. El problema se extiende también al ámbito del cumplimiento de las medidas de seguridad. El funcionamiento de las instituciones públicas en esta materia parece deficitario debido principalmente a una escasez de recursos materiales; la principal consecuencia es una falta de coordinación entre las necesidades terapéuticas y asistenciales, por lo que se opta por una prevalencia del modelo regimental propio de las prisiones. Nos encontramos con una materia en la que los elementos regimentales y terapéuticos confluyen, se confunden y llegan a aplicarse indebidamente.The nature and perception of mental health has changed throughout history and has had a different influence on diverse communities. The focus on it as part of health in general is relatively recent. The influence of this matter in the criminal and penitentiary sphere has been reflected in certain legal texts and international agreements, but its greatest development comes essentially from the Instructions of the General Secretariat of Penitentiary Institutions.The regimental element by which the activity of penitentiary establishments are influenced is complemented by care and resocialization needs that cannot be avoided. Mechanisms have been articulated for the treatment of mental health in the prison population in general and in particular those subjects who suffer from mental illness. The problem extends to security measures. The work of public institutions in this matter seems to be lacking, mainly due to a lack of material resources; the main consequence is a lack of coordination between therapeutic and care needs, which is why a prevalence of the regimental model of prisons is chosen. We are in fronto of a matter in which the regimental and therapeutic elements come together, are confused and are improperly applied.Departamento de Derecho Penal e Historia y Teoría del DerechoGrado en Derech

The treatment of affective-sexual diversity in Secondary Education in the English class

La homofobia es motivo de bullying en las aulas y abordarlo requiere una formación específica por parte del profesorado. Resulta fundamental el conocimiento conceptual de las orientaciones sexuales y de la identificación de género, la influencia del heterosexismo, la heteronormatividad y la heteromasculinidad en la construcción social de la persona. Desde la primera década del siglo XXI se proponen la aplicación de nuevas pedagogías, como la queer, para la formación en el amor, respeto y tolerancia. Se presenta una propuesta de intervención educativa en el aula de “Lengua Extranjera: Inglés” dirigida a alumnos de 3º de la ESO.Homophobia is a reason for bullying in the classrooms and addressing it requires specific training by teachers. Is essential the conceptual knowledge of sexual orientations and gender identification, but also the influence of heterosexism, heteronormativity and heteromasculinity in the social construction of the person. Since the first decade of the twenty-first century different experiences have been carried out and some researchers have suggested new pedagogies such as queer, toward the formation of students in love, respect and tolerance. we will present a proposal for educational intervention in the classroom of "Foreign Language: English" to 3rd grade of secondary students

Recursos para la incorporación de la Agenda 2030 a la Programación Didáctica en la asignatura de Economía

Presentar una serie de recursos para la elaboración de una Programación Didáctica innovadora en la que propongo la incorporación de la Agenda 2030 al curriculum de la Asignatura de Economía de 1ª de BachilleratoDepartamento de Didáctica de las Ciencias Sociales y ExperimentalesMáster en Profesor de Educación Secundaria Obligatoria y Bachillerato, Formación Profesional y Enseñanzas de Idiomas (Especialidad: Economía

Magnetism, spin texture and in-gap states: Atomic specialization at the surface of oxygen-deficient SrTiO3_3

Motivated by recent spin- and angular-resolved photoemission (SARPES) measurements performed on the two-dimensional electronic states confined near the (001) surface of SrTiO$_3$ in the presence of oxygen vacancies, we explore their spin structure by means of ab initio density functional theory (DFT) calculations of slabs. Relativistic nonmagnetic DFT calculations display Rashba-like spin winding with a splitting of a few meV and when surface magnetism on the Ti ions is in- cluded, bands become spin-split with an energy difference ~100 meV at the $\Gamma$ point, consistent with SARPES findings. While magnetism tends to suppress the effects of the relativistic Rashba interaction, signatures of it are still clearly visible in terms of complex spin textures. Furthermore, we observe an atomic specialization phenomenon, namely, two types of electronic contributions: one is from Ti atoms neighboring the oxygen vacancies that acquire rather large magnetic moments and mostly create in-gap states; another comes from the partly polarized t$_{2g}$ itinerant electrons of Ti atoms lying further away from the oxygen vacancy, which form the two-dimensional electron system and are responsible for the Rashba spin winding and the spin splitting at the Fermi surface.Comment: 6 pages, 4 figures, for Suppl. Mat. please contact first autho

CXCR4/CXCR7 molecular involvement in neuronal and neural progenitor migration: Focus in CNS repair

© 2014 Wiley Periodicals, Inc.In the adult brain, neural progenitor cells (NPCs) reside in the subventricular zone (SVZ) of the lateral ventricles, the dentate gyrus and the olfactory bulb. Following CNS insult, NPCs from the SVZ can migrate along the rostral migratory stream (RMS), a migration of NPCs that is directed by proinflammatory cytokines. Cells expressing CXCR4 follow a homing signal that ultimately leads to neuronal integration and CNS repair, although such molecules can also promote NPC quiescence. The ligand, SDF1 alpha (or CXCL12) is one of the chemokines secreted at sites of injury that it is known to attract NSC-derived neuroblasts, cells that express CXCR4. In function of its concentration, CXCL12 can induce different responses, promoting NPC migration at low concentrations while favoring cell adhesion via EGF and the alpha 6 integrin at high CXCL12 concentrations. However, the preclinical effectiveness of chemokines and their relationship with NPC mobilization requires further study, particularly with respect to CNS repair. NPC migration may also be affected by the release of cytokines or chemokines induced by local inflammation, through autocrine or paracrine mechanisms, as well as through erythropoietin (EPO) or nitric oxide (NO) release. CXCL12 activity requires G-coupled proteins and the availability of its ligand may be modulated by its binding to CXCR7, for which it shows a stronger affinity than for CXCR4Comision Interministerial de Ciencia y Tecnologíä (Grant SAF 2012-3127) and the “Ramon y Cajal” programme (RyC 2008-0258 to JJM and RyC 2010-06251 to B.C). We also thank Fundación Ramón Areces for its institutional support of the “Centro de Biología Molecular Severo Ochoa”.Peer Reviewe

R-ras1 and r-ras2 are essential for oligodendrocyte differentiation and survival for correct myelination in the central nervous system

Rapid and effective neural transmission of information requires correct axonal myelination. Modifications in myelination alter axonal capacity to transmit electric impulses and enable pathological conditions. In the CNS, oligodendrocytes (OLs) myelinate axons, a complex process involving various cellular interactions. However, we know little about the mechanisms that orchestrate correct myelination. Here, we demonstrate that OLs express R-Ras1 and R-Ras2. Using female and male mutant mice to delete these proteins, we found that activation of the PI3K/Akt and Erk1/2-MAPK pathways was weaker in mice lacking one or both of these GTPases, suggesting that both proteins coordinate the activity of these two pathways. Loss of R-Ras1 and/or R-Ras2 diminishes the number of OLs in major myelinated CNS tracts and increases the proportion of immature OLs. In R-Ras1-/-and R-Ras2-/--null mice, OLs show aberrant morphologies and fail to differentiate correctly into myelin-forming phenotypes. The smaller OL population and abnormal OL maturation induce severe hypomyelination, with shorter nodes of Ranvier in R-Ras1-/-and/or R-Ras2-/-mice. These defects explain the slower conduction velocity of myelinated axons that we observed in the absence of R-Ras1 and R-Ras2. Together, these results suggest that R-Ras1 and R-Ras2 are upstream elements that regulate the survival and differentiation of progenitors into OLs through the PI3K/Akt and Erk1/2-MAPK pathways for proper myelination.This work was supported by the Spanish Ministry of Economy and Competitiveness (BFU2015-64829-S and SAF2012-31279) to B.C. and (SAF2015-70368-R) to F.W

Hipótesis glutamatérgica de la esquizofrenia: mecanismos moleculares del transporte de glicina en las sinapsis glutamatérgicas

During the last few years, evidence has been obtained for a relationship between hypofunction of the NMDA type of glutamate receptor and schizophrenia. The glycine binding site on NMDAR and the glycine transporter GLYT1 represent some of the most promising therapeutic targets for developing new anti-schizophrenic drugs. Pharmacological inhibition of GLYT1 increases glycine levels in the surrounding of NMDAR and stimulates its function. Previous studies performed indicated that GLYT1 is physically associated with NMDAR, through the scaffolding protein PSD-95, due to the common interaction of both GLYT1 and NMDAR with PDZ domains of PSD-95. The objective of this research was centred on the study of the interaction of GLYT1 with other PDZ proteins, in special those that also interact with NMDAR. Particularly, we were interested the heteromeric tricomplex Mint-MALS-CASK. We analyzed the structural basis of these interactions and the functional consequence on GLYT1 in aspects such as the intracellular traffic, the turnover on the cell surface and the inclusion in specific microdomains of the membrane. In this way we analyzed the possible existence of common steps in GLYT1 and NMDAR processing. To do that we used molecular and cellular biology techniques, such as cotransfections in cellular systems of DNA constructs obtained by site directed mutagenesis and immunoprecipitations.Durante los últimos años, se han obtenido evidencias que relacionan la hipofunción del receptor de glutamato tipo NMDA (NMDAR) con la esquizofrenia. Los receptores NMDA necesitan para su estimulación la unión conjunta tanto de glutamato como de glicina, ya que ambos poseen en el receptor un sitio de unión específico. Puesto que la inhibición farmacológica de GLYT1 aumenta los niveles de glicina en los alrededores del receptor de glutamato tipo NMDA estimulando su función, el transportador de glicina GLYT1 representa una de las dianas terapéuticas más prometedoras para el desarrollo de nuevos fármacos antipsicóticos. Previamente hemos demostrado que GLYT1 se encuentra físicamente asociado con NMDAR a través de la proteína de adaptadora PSD-95 en neuronas glutamatérgicas. El objetivo de este trabajo se centra en el estudio de la interacción de GLYT1 con otras proteínas, especialmente con aquellas que también interaccionan con el receptor de glutamato tipo NMDA. Hemos encontrado que GLYT1 interacciona con el tricomplejo heterotrimérico Mint-MALS-CASK. Este complejo está implicado en el transporte polarizado del receptor del glutamato tipo NMDA al terminal postsináptico. Puesto que GLYT1 interacciona simultáneamente con NMDAR y con el complejo Mint-MALS-CASK, proponemos que NMDAR y GLYT1 son cotransportados al terminal sináptico, así en todo momento NMDAR puede ser regulado por GLYT1. Estos resultados refuerzan la importancia de GLYT1 en la regulación de NMDAR y su potencial como blanco de acción de fármacos antipsicóticos

R-RAS2 overexpression in tumors of the human central nervous system

Malignant tumors of the central nervous system (CNS) are the 10th most frequent cause of cancer mortality. Despite the strong malignancy of some such tumors, oncogenic mutations are rarely found in classic members of the RAS family of small GTPases. This raises the question as to whether other RAS family members may be affected in CNS tumors, excessively activating RAS pathways. The RAS-related subfamily of GTPases is that which is most closely related to classical Ras and it currently contains 3 members: RRAS, RRAS2 and RRAS3. While R-RAS and R-RAS2 are expressed ubiquitously, R-RAS3 expression is restricted to the CNS. Significantly, both wild type and mutated RRAS2 (also known as TC21) are overexpressed in human carcinomas of the oral cavity, esophagus, stomach, skin and breast, as well as in lymphomas. Hence, we analyzed the expression of R-RAS2 mRNA and protein in a wide variety of human CNS tumors and we found the R-RAS2 protein to be overexpressed in all of the 90 CNS cancer samples studied, including glioblastomas, astrocytomas and oligodendrogliomas. However, R-Ras2 was more strongly expressed in low grade (World Health Organization grades I-II) rather than high grade (grades III-IV) tumors, suggesting that R-RAS2 is overexpressed in the early stages of malignancy. Indeed, R-RAS2 overexpression was evident in pre-malignant hyperplasias, both at the mRNA and protein levels. Nevertheless, such dramatic changes in expression were not evident for the other two subfamily members, which implies that RRAS2 is the main factor triggering neural transformation.This work was supported by grants SAF2012-31279 from the ‘Comisión Interministerial de Ciencia y Tecnología’ and the ‘Ramón y Cajal’ program (RYC-2010-06251, to B.C.). We also thank the Fundación Ramón Areces for its institutional support of the ‘Centro de Biología Molecular Severo Ochoa’