The role of the synaptic protein SV2B in embryonic development of the cerebral cortex

The mammalian cerebral cortex experienced an extraordinary expansion during evolution, concomitant with an increase in complexity and cognitive capacities. The increase in cortical surface area appeared along with folding, which allowed including a large cortical surface within a limited cranial volume. This evolutionary process is recapitulated during embryonic development, where the activity of progenitor cells determines the final brain conformation. Apical Radial Glia Cells (aRGCs) are the main type of progenitor cells in the cerebral cortex, forming the Ventricular Zone (VZ). aRGCs give rise to Intermediate Progenitor Cells (IPCs) and basal Radial Glia Cells (bRGCs), that populate the Subventricular Zone (SVZ). In gyrencephalic species, with a folded cortex as ferrets or humans, the SVZ is dramatically enlarged and subdivided into inner and outer domains (ISVZ and OSVZ), densely populated by bRGCs and playing critical roles in cortex expansion and folding. In ferret, aRGCs switch from amplificative divisions to produce massive amounts of bRGCs during a brief period, which will establish the OSVZ. Disruptions in bRGC production profoundly impair OSVZ formation, altering normal folding. In the ferret VZ several genes change their expression levels during development, in parallel with the dynamics of aRGCs forming bRGCs and the emergence of the OSVZ. These genes are promising candidates to regulate this process and, therefore, cortical folding. One of these candidates is Sv2b, which encodes for the Synaptic Vesicle Glycoprotein 2B, with not known function in progenitor cells or cerebral cortex development. In this thesis, we show that in the small and smooth mouse cortex, with very few bRGCs, Sv2b is not expressed in germinal layers. In contrast, in the big and folded ferret brain Sv2b is highly expressed in germinal layers, dynamically changing its expression before, during and after the critical period for bRGCs generation. Sv2b is downregulated during the critical period and later on upregulated. Moreover, when bRGCs are being massively produced, Sv2b is more expressed in the SVZ than the VZ. We have found that SV2B accumulates in subcellular compartments of aRGCs, including varicosities of the processes and the end-feet. By gain- and loss-of-function experiments in mouse and ferret, we have found that SV2B is involved in the laminar organization of the VZ, the delamination of aRGCs to basal positions, and their proliferation. At mid-term, these alterations lead to folding of the cortex. Experimental overexpression of SV2B in ferret during the critical period, when endogenous Sv2b expression is low, causes a reduction in proliferation and neurogenesis. Conversely, Sv2b removal from aRGCs induces an increase in proliferation and basal mitoses. Thus, levels of Sv2b expression regulate the proliferative activity of aRGCs and the production of bRGCs during cerebral cortex development

Pathogenic Variants Associated with Epigenetic Control and the NOTCH Pathway Are Frequent in Classic Hodgkin Lymphoma

Classic Hodgkin lymphoma (cHL) constitutes a B-cell neoplasm derived from germinal center lymphocytes. Despite high cure rates (80–90%) obtained with the current multiagent protocols, a significant proportion of cHL patients experience recurrences, characterized by a lower sensitivity to second-line treatments. The genomic background of chemorefractory cHL is still poorly understood, limiting personalized treatment strategies based on molecular features. In this study, using a targeted next-generation sequencing (NGS) panel specifically designed for cHL research, we compared chemosensitive and chemorefractory diagnostic tissue samples of cHL patients. Furthermore, we longitudinally examined paired diagnosis–relapsesamples of chemorefractory cHL in order to define patterns of dynamic evolution and clonal selection. Pathogenic variants in NOTCH1 and NOTCH2 genes frequently arise in cHL. Mutations in genes associated with epigenetic regulation (CREBBP and EP300) are particularly frequent in relapsed/refractory cHL. The appearance of novel clones characterized by mutations previously not identified at diagnosis is a common feature in cHL cases showing chemoresistance to frontline treatments. Our results expand current molecular and pathogenic knowledge of cHL and support the performance of molecular studies in cHL prior to the initiation of first-line therapies

Secondary loss of miR-3607 reduced cortical progenitor amplification during rodent evolution

The evolutionary expansion and folding of the mammalian cerebral cortex resulted from amplification of progenitor cells during embryonic development. This process was reversed in the rodent lineage after splitting from primates, leading to smaller and smooth brains. Genetic mechanisms underlying this secondary loss in rodent evolution remain unknown. We show that microRNA miR-3607 is expressed embryonically in the large cortex of primates and ferret, distant from the primate-rodent lineage, but not in mouse. Experimental expression of miR-3607 in embryonic mouse cortex led to increased Wnt/β-catenin signaling, amplification of radial glia cells (RGCs), and expansion of the ventricular zone (VZ), via blocking the β-catenin inhibitor APC (adenomatous polyposis coli). Accordingly, loss of endogenous miR-3607 in ferret reduced RGC proliferation, while overexpression in human cerebral organoids promoted VZ expansion. Our results identify a gene selected for secondary loss during mammalian evolution to limit RGC amplification and, potentially, cortex size in rodents.This work was supported by Santiago Grisolía predoctoral fellowship (K.C.), Generalitat Valenciana I+D+i programs grant APOSTD/2019/059 (A.C.), Fundación Tatiana Pérez de Guzmán el Bueno predoctoral fellowship (A.P.-C.), Agencia Estatal de Investigación SVP-2014-068671 (A.V.), Spanish State Research Agency FPI contract (R.S.), Spanish State Research Agency grant RYC-2015-18056 (J.P.L.-A.), Spanish State Research Agency grant RTI2018-102260-B-100 (J.P.L.-A.), Spanish State Research Agency grant SAF2015-69168-R (V.B.), Spanish State Research Agency grant PGC2018-102172-B-I00 (V.B.), Spanish State Research Agency “Severo Ochoa” Programme for Centers of Excellence in R&D grant SEV-2017-0723 (V.B.), and European Research Council grant 309633 (V.B.).Peer reviewe

Tropical tree growth driven by dry-season climate variability

Interannual variability in the global land carbon sink is strongly related to variations in tropical temperature and rainfall. This association suggests an important role for moisture-driven fluctuations in tropical vegetation productivity, but empirical evidence to quantify the responsible ecological processes is missing. Such evidence can be obtained from tree-ring data that quantify variability in a major vegetation productivity component: woody biomass growth. Here we compile a pantropical tree-ring network to show that annual woody biomass growth increases primarily with dry-season precipitation and decreases with dry-season maximum temperature. The strength of these dry-season climate responses varies among sites, as reflected in four robust and distinct climate response groups of tropical tree growth derived from clustering. Using cluster and regression analyses, we find that dry-season climate responses are amplified in regions that are drier, hotter and more climatically variable. These amplification patterns suggest that projected global warming will probably aggravate drought-induced declines in annual tropical vegetation productivity. Our study reveals a previously underappreciated role of dry-season climate variability in driving the dynamics of tropical vegetation productivity and consequently in influencing the land carbon sink.We acknowledge financial support to the co-authors provided by Agencia Nacional de Promoción Científica y Tecnológica, Argentina (PICT 2014-2797) to M.E.F.; Alberta Mennega Stichting to P.G.; BBVA Foundation to H.A.M. and J.J.C.; Belspo BRAIN project: BR/143/A3/HERBAXYLAREDD to H.B.; Confederação da Agricultura e Pecuária do Brasil - CNA to C.F.; Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES, Brazil (PDSE 15011/13-5 to M.A.P.; 88881.135931/2016-01 to C.F.; 88887.199858/2018-00 to G.A.-P.; Finance Code 001 for all Brazilian collaborators); Conselho Nacional de Desenvolvimento Científico e Tecnológico - CNPq, Brazil (ENV 42 to O.D.; 1009/4785031-2 to G.C.; 311874/2017-7 to J.S.); CONACYT-CB-2016-283134 to J.V.-D.; CONICET to F.A.R.; CUOMO FOUNDATION (IPCC scholarship) to M.M.; Deutsche Forschungsgemeinschaft - DFG (BR 1895/15-1 to A.B.; BR 1895/23-1 to A.B.; BR 1895/29-1 to A.B.; BR 1895/24-1 to M.M.); DGD-RMCA PilotMAB to B.T.; Dirección General de Asuntos del Personal Académico of the UNAM (Mexico) to R.B.; Elsa-Neumann-Scholarship of the Federal State of Berlin to F.S.; EMBRAPA Brazilian Agricultural Research Corporation to C.F.; Equatorian Dirección de Investigación UNL (21-DI-FARNR-2019) to D.P.-C.; São Paulo Research Foundation FAPESP (2009/53951-7 to M.T.-F.; 2012/50457-4 to G.C.; 2018/01847‐0 to P.G.; 2018/24514-7 to J.R.V.A.; 2019/08783-0 to G.M.L.; 2019/27110-7 to C.F.); FAPESP-NERC 18/50080-4 to G.C.; FAPITEC/SE/FUNTEC no. 01/2011 to M.A.P.; Fulbright Fellowship to B.J.E.; German Academic Exchange Service (DAAD) to M.I. and M.R.; German Ministry of Education, Science, Research, and Technology (FRG 0339638) to O.D.; ICRAF through the Forests, Trees, and Agroforestry research programme of the CGIAR to M.M.; Inter-American Institute for Global Change Research (IAI-SGP-CRA 2047) to J.V.-D.; International Foundation for Science (D/5466-1) to M.I.; Lamont Climate Center to B.M.B.; Miquelfonds to P.G.; National Geographic Global Exploration Fund (GEFNE80-13) to I.R.; USA’s National Science Foundation NSF (IBN-9801287 to A.J.L.; GER 9553623 and a postdoctoral fellowship to B.J.E.); NSF P2C2 (AGS-1501321) to A.C.B., D.G.-S. and G.A.-P.; NSF-FAPESP PIRE 2017/50085-3 to M.T.-F., G.C. and G.M.L.; NUFFIC-NICHE programme (HEART project) to B.K., E.M., J.H.S., J.N. and R. Vinya; Peru ‘s CONCYTEC and World Bank (043-2019-FONDECYT-BM-INC.INV.) to J.G.I.; Peru’s Fondo Nacional de Desarrollo Científico, Tecnológico y de Innovación Tecnológica (FONDECYT-BM-INC.INV 039-2019) to E.J.R.-R. and M.E.F.; Programa Bosques Andinos - HELVETAS Swiss Intercooperation to M.E.F.; Programa Nacional de Becas y Crédito Educativo - PRONABEC to J.G.I.; Schlumberger Foundation Faculty for the Future to J.N.; Sigma Xi to A.J.L.; Smithsonian Tropical Research Institute to R. Alfaro-Sánchez.; Spanish Ministry of Foreign Affairs AECID (11-CAP2-1730) to H.A.M. and J.J.C.; UK NERC grant NE/K01353X/1 to E.G.Peer reviewe

Going back in time with TEMPO

In this issue of Neuron, Espinosa-Medina et al.1 present the TEMPO (Temporal Encoding and Manipulation in a Predefined Order) system, which enables the marking and genetic manipulation of sequentially generated cell lineages in vertebrate species in vivo

Role of endothelin 3 - endothelin receptor B signalingin cerebral cortex development

Trabajo presentado al 18th National Meeting of the Spanish Society of Neuroscience (SENC), celebrado en Santiago de Compostela del 4 al 6 de septiembre de 2019.Peer reviewe

The role of the synaptic protein SV2B in embryonic development of the cerebral cortex

Trabajo presentado al 18th National Meeting of the Spanish Society of Neuroscience (SENC), celebrado en Santiago de Compostela del 4 al 6 de septiembre de 2019.Peer reviewe

Interplay of Cell‐autonomous Gene Function and Tissue‐wide Mechanisms Regulating Radial Glial Progenitor Lineage Progression

The cerebral cortex is comprised of a vast cell-type diversity sequentially generated by cortical progenitor cells. Faithful progenitor lineage progression requires the tight orchestration of distinct molecular and cellular mechanisms regulating proper progenitor proliferation behavior and differentiation. Correct execution of developmental programs involves a complex interplay of cell intrinsic and tissue-wide mechanisms. Many studies over the past decades have been able to determine a plethora of genes critically involved in cortical development. However, only a few made use of genetic paradigms with sparse and global gene deletion to probe cell-autonomous vs. tissue-wide contribution. In this chapter, we will elaborate on the importance of dissecting the cell-autonomous and tissue-wide mechanisms to gain a precise understanding of gene function during radial glial progenitor lineage progression

Pathogenic Variants Associated with Epigenetic Control and the NOTCH Pathway Are Frequent in Classic Hodgkin Lymphoma

Classic Hodgkin lymphoma (cHL) constitutes a B-cell neoplasm derived from germinal center lymphocytes. Despite high cure rates (80–90%) obtained with the current multiagent protocols, a significant proportion of cHL patients experience recurrences, characterized by a lower sensitivity to second-line treatments. The genomic background of chemorefractory cHL is still poorly understood, limiting personalized treatment strategies based on molecular features. In this study, using a targeted next-generation sequencing (NGS) panel specifically designed for cHL research, we compared chemosensitive and chemorefractory diagnostic tissue samples of cHL patients. Furthermore, we longitudinally examined paired diagnosis–relapsesamples of chemorefractory cHL in order to define patterns of dynamic evolution and clonal selection. Pathogenic variants in NOTCH1 and NOTCH2 genes frequently arise in cHL. Mutations in genes associated with epigenetic regulation (CREBBP and EP300) are particularly frequent in relapsed/refractory cHL. The appearance of novel clones characterized by mutations previously not identified at diagnosis is a common feature in cHL cases showing chemoresistance to frontline treatments. Our results expand current molecular and pathogenic knowledge of cHL and support the performance of molecular studies in cHL prior to the initiation of first-line therapies

La idea de frontera : estudio del patrimonio natural y cultural de Ágreda

Este proyecto de innovación educativa se presentó en el Congreso Internacional de Innovación en la Educación celebrado en Valladolid los dias 26, 27 y 28 de abril de 2005El Instituto de Enseñanza Secundaria 'Margarita de Fuenmayor' se encuentra en el extremo este de la comunidad autónoma de Castilla y León, colindante con la de Aragón. Su patrimonio es una mezcla de caracteres castellanos, aragoneses y navarros; en una idea de frontera física y cultural. Esta situación fronteriza ha elicitado en su historia la convivencia de tres culturas: cristiana, árabe y judía. Esta peculiaridad es el eje conductor de este proyecto, en un estudio comparativo de la diversidad de Castilla y León. Los objetivos propuestos son: aunar las iniciativas de los distintos departamentos con un eje conductor común de trabajo; diseñar acciones formativas de cara a una posible impartición de una materia o contenido dentro de una materia como es el patrimonio de la comunidad de Castilla y León; entresacar los distintos aspectos naturales y culturales sobre un mismo tema en un trabajo de interdisciplinariedad; responder a las iniciativas y necesidades innovadoras del claustro de profesores del centro; hacer partícipe al resto del profesorado del centro de unos materiales propios e inéditos; articular unos objetivos y unos contenidos didácticos con una propuesta clara de trabajo y aplicación dentro del aula, encontrar un foro compartido de esfuerzo y trabajo en equipo dentro del centro; propiciar el encuentro de experiencias sobre el tema de innovación, indagar en fuentes de investigación locales y provinciales. El equipo docente del centro se propone la elaboración de materiales didácticos sobre el patrimonio de Castilla y León y al mismo tiempo dar a conocer una serie de iniciativas que sobre la investigación del patrimonio cultural se están llevando a cabo por varios miembros del claustro. La metodología de trabajo por un lado es de recopilación e indagación científica e histórica sobre el entorno físico y artístico de la zona, complementándose en una primera fase con una labor de investigación científica, cultural y lingüística sobre los aspectos reseñados; posteriormente un periodo eminentemente didáctico de elaboración de materiales con las últimas tecnologías de cara a una aplicación directa en el aula o en las distintas áreas que a su vez comprenden distintos departamentos. La organización del trabajo, se divide en cuatro partes: 1ú Reuniones de todos los participantes en el proyecto, en las que se ha distribuido el trabajo para realizar en grupos más pequeños o individualmente. Este material elaborado por los distintos departamentos se ponía en común con los demás miembros del grupo, para ir realizando -entre todos- el guión que luego los encargados de la maquetación utilizarían para dar la apariencia final al proyecto: CD y actividades.2ú Reuniones por departamentos (grupos más pequeños): cada departamento o grupos de departamentos (áreas de contenidos afines) trabaja centrado en su tema: Estudio comparativo y diferencial de las culturas cristianas, judías y árabes en la Edad Media ( Arte. Mercado. La ciudad. Alimentación. Religión. Música. Vestido. Oficios. La Tecnología. (Unidades de medida. Constelaciones y alquimia. ) ; Estudio comparativo y diferencial del medio natural respecto a las cuencas del Duero y del Ebro ( La frontera vegetal. La frontera animal. La frontera del agua. La frontera del clima. La frontera mineral.) ; Apoyo lingüístico a las dos áreas generales . Elaboración de glosario; Apoyo pedagógico para la elaboración de actividades. Actividades sobre el tema 'La mujer'. 3- Trabajo de investigación y recopilación de materiales realizado en grupos o individualmente: búsqueda de imágenes, música, trabajo de investigación de archivo y búsqueda de documentación. 4- Trabajo individual: individualmente o en grupo se digitalizan imágenes y texto. El resultado final es un material didáctico sobre el patrimonio natural y cultural de la vertiente oriental de Castilla y León, realizado pensando en los alumnos de cuarto curso de educación secundaria presentado en dos apartados: el CD y láminas de actividades complementarias.Junta de Castilla y LeónCastilla y LeónConsejería de Educación. Dirección General de Universidades e Investigación; Monasterio de Nuestra Señora de Prado, Autovía Puente Colgante, s. n.; 47071 Valladolid; Tel. +34983411881; Fax +34983411939ES