Dopaminergic control of ADAMTS2 expression through cAMP/CREB and ERK: molecular effects of antipsychotics

© The Author(s) 2019.A better understanding of the molecular mechanisms that participate in the development and clinical manifestations of schizophrenia can lead to improve our ability to diagnose and treat this disease. Previous data strongly associated the levels of deregulated ADAMTS2 expression in peripheral blood mononuclear cells (PBMCs) from patients at first episode of psychosis (up) as well as in clinical responders to treatment with antipsychotic drugs (down). In this current work, we performed an independent validation of such data and studied the mechanisms implicated in the control of ADAMTS2 gene expression. Using a new cohort of drug-naïve schizophrenia patients with clinical follow-up, we confirmed that the expression of ADAMTS2 was highly upregulated in PBMCs at the onset (drug-naïve patients) and downregulated, in clinical responders, after treatment with antipsychotics. Mechanistically, ADAMTS2 expression was activated by dopaminergic signalling (D1-class receptors) and downstream by cAMP/CREB and mitogen-activated protein kinase (MAPK)/ERK signalling. Incubation with antipsychotic drugs and selective PKA and MEK inhibitors abrogated D1-mediated activation of ADAMTS2 in neuronal-like cells. Thus, D1 receptors signalling towards CREB activation might participate in the onset and clinical responses to therapy in schizophrenia patients, by controlling ADAMTS2 expression and activity. The unbiased investigation of molecular mechanisms triggered by antipsychotic drugs may provide a new landscape of novel targets potentially associated with clinical efficacy.This work was supported by: SAF2016-76046-R and SAF2013-46292-R (MINECO and FEDER) to B.C.F., PI16/00156 (isciii and FEDER) to J.P.V., LUCHAMOS POR LA VIDA project to F.R.J. and J.P.V., SAF2017-83702-R (MINECO and FEDER), Red TERCEL RD12/0019/0024 (ISCIII) and GVA-PROMETEO 2018/041 (Generalitat Valenciana) to S.M. J.P.V. is supported by the RyC research programme (RYC-2013-14097) and F.R.J. by the predoctoral research programme (BES-2014-070615), from MINECO and FEDER

Dopaminergic control of ADAMTS2 expression through cAMP/CREB and ERK: molecular effects of antipsychotics

A better understanding of the molecular mechanisms that participate in the development and clinical manifestations of schizophrenia can lead to improve our ability to diagnose and treat this disease. Previous data strongly associated the levels of deregulated ADAMTS2 expression in peripheral blood mononuclear cells (PBMCs) from patients at first episode of psychosis (up) as well as in clinical responders to treatment with antipsychotic drugs (down). In this current work, we performed an independent validation of such data and studied the mechanisms implicated in the control of ADAMTS2 gene expression. Using a new cohort of drug-naïve schizophrenia patients with clinical follow-up, we confirmed that the expression of ADAMTS2 was highly upregulated in PBMCs at the onset (drug-naïve patients) and downregulated, in clinical responders, after treatment with antipsychotics. Mechanistically, ADAMTS2 expression was activated by dopaminergic signalling (D1-class receptors) and downstream by cAMP/CREB and mitogen-activated protein kinase (MAPK)/ERK signalling. Incubation with antipsychotic drugs and selective PKA and MEK inhibitors abrogated D1-mediated activation of ADAMTS2 in neuronal-like cells. Thus, D1 receptors signalling towards CREB activation might participate in the onset and clinical responses to therapy in schizophrenia patients, by controlling ADAMTS2 expression and activity. The unbiased investigation of molecular mechanisms triggered by antipsychotic drugs may provide a new landscape of novel targets potentially associated with clinical efficacy.Acknowledgements: We are highly indebted to the participants and their families for their cooperation in this study. We also thank IDIVAL biobank (Inés Santiuste and Jana Arozamena) for clinical samples and data as well as the PAFIP members (Marga Corredera) for the data collection. This work was supported by: SAF2016-76046-R and SAF2013-46292-R (MINECO and FEDER) to B.C.F., PI16/00156 (isciii and FEDER) to J.P.V., LUCHAMOS POR LA VIDA project to F.R.J. and J.P.V., SAF2017-83702-R (MINECO and FEDER), Red TERCEL RD12/0019/0024 (ISCIII) and GVA-PROMETEO 2018/041 (Generalitat Valenciana) to S.M. J.P.V. is supported by the RyC research programme (RYC-2013-14097) and F.R.J. by the predoctoral research programme (BES-2014-070615), from MINECO and FEDER

Abstracts from the 20th International Symposium on Signal Transduction at the Blood-Brain Barriers

https://deepblue.lib.umich.edu/bitstream/2027.42/138963/1/12987_2017_Article_71.pd

Telencephalic morphogenesis during the process of neurulation: An experimental study using quail-chick chimeras

After gastrulation, during the process of neurulation, the anterior neural region undergoes important morphological transformations. The almost flat epithelium of the rostral neural plate becomes transformed into a spherical region, the prosencephalic vesicle, in the neural tube. Later in development, two bilateral areas (the optic and telencephalic vesicles) progressively protrude from the prosencephalon, generating the eyes and the cerebral hemispheres, respectively. Although the principal processes of neurulation have been well characterized, the growth patterns and evolution of topological relations between internal prosencephalic regions have not been experimentally analyzed. In order to better characterize morphogenetic transformations of the prosencephalon, we have realized and comparatively analyzed neuroepithelial fate maps before and after neurulation using quail/chick chimerical experiments. Since we have previously reported the fate map of the prosencephalon at the neural plate stage, in the present work we report the corresponding fate map at the neural tube stage. Comparative analysis of the two maps has allowed us to descriptively characterize the morphogenetic transformations of the alar prosencephalic regions during neurulation and to establish the topologic evolution of the principal areas of the vertebrate telencephalon.Grant sponsor: DIGESIC-MEC; Grant number: BFU2005-09085 (to A.P.); Grant sponsor: Ingenio 2010 MEC-CONSOLIDER; Grant number: CSD2007-00023; Grant sponsor: IP from EU; Grant sponsor: LSHG-CT-2004-512003.Peer Reviewe

Radial glia fibers translate Fgf8 morphogenetic signals to generate a thalamic nuclear complex protomap in the mantle layer

Thalamic neurons are distributed between different nuclear groups of the thalamic multinuclear complex; they develop topologically ordered specific projections that convey information on voluntary motor programs and sensory modalities to functional areas in the cerebral cortex. Since thalamic neurons present a homogeneous morphology, their functional specificity is derived from their afferent and efferent connectivity. Adequate development of thalamic afferent and efferent connections depends on guide signals that bind receptors in nuclear neuropils and axonal growth cones, respectively. These are finally regulated by regionalization processes in the thalamic neurons, codifying topological information. In this work, we studied the role of Fgf8 morphogenetic signaling in establishing the molecular thalamic protomap, which was revealed by Igsf21, Pde10a and Btbd3 gene expression in the thalamic mantle layer. Fgf8 signaling activity was evidenced by pERK expression in radial glia cells and fibers, which may represent a scaffold that translates neuroepithelial positional information to the mantle layer. In this work, we describe the fact that Fgf8-hypomorphic mice did not express pERK in radial glia cells and fibers and presented disorganized thalamic regionalization, increasing neuronal death in the ventro-lateral thalamus and strong disruption of thalamocortical projections. In conclusion, Fgf8 encodes the positional information required for thalamic nuclear regionalization and the development of thalamocortical projections.This work was supported by the Spanish Ministry of Science and Innovation grant:FEDER BFU2011-27326, SAF2014-59347-C2-1-R, and Severo Ochoa Excellence Project SEV-2013-0317; ISCIII: Red TERCEL RD12/0019/0024, and CIBERSAM; GVA: PROMETEO II/2014/014, and the WOP Association.Peer reviewe

Pericyte–Glioblastoma Cell Interaction: A Key Target to Prevent Glioblastoma Progression

Multiple biological processes rely on direct intercellular interactions to regulate cell proliferation and migration in embryonic development and cancer processes. Tumor development and growth depends on close interactions between cancer cells and cells in the tumor microenvironment. During embryonic development, morphogenetic signals and direct cell contacts control cell proliferation, polarity, and morphogenesis. Cancer cells communicate with cells in the tumor niche through molecular signals and intercellular contacts, thereby modifying the vascular architecture and antitumor surveillance processes and consequently enabling tumor growth and survival. While looking for cell-to-cell signaling mechanisms that are common to both brain development and cancer progression, we have studied the infiltration process in glioblastoma multiforme (GBM), which is the most malignant primary brain tumor and with the worst prognosis. Cell-to-cell contacts, by means of filopodia-like structures, between GBM cells and brain pericytes (PCs) are necessary for adequate cell signaling during cancer infiltration; similarly, contacts between embryonic regions, via cytonemes, are required for embryo regionalization and development. This GBM–PC interaction provokes two important changes in the physiological function of these perivascular cells, namely, (i) vascular co-option with changes in cell contractility and vascular malformation, and (ii) changes in the PC transcriptome, modifying the microvesicles and protein secretome, which leads to the development of an immunosuppressive phenotype that promotes tumor immune tolerance. Moreover, the GTPase Cdc42 regulates cell polarity across organisms, from yeast to humans, playing a central role in GBM cell–PC interaction and maintaining vascular co-option. As such, a review of the molecular and cellular mechanisms underlying the development and maintenance of the physical interactions between cancer cells and PCs is of particular interest

Fate map of the chick embryo neural tube

Fate-map studies have provided important information in relation to the regional topology of brain areas in different vertebrate species. Moreover, these studies have demonstrated that the distribution of presumptive territories in neural plate and neural tube are highly conserved in vertebrates. The aim of this review is to re-examine and correlate the distribution of presumptive neuroepithelial domains in the chick neural tube with molecular information and discuss recent data. First, we review descriptive fate map studies of neural plate in different vertebrate species that have been studied using diverse fate-mapping methods. Then, we summarize the available data on the localization of neuroepithelial progenitors for the brain subregions in the chick neural tube at stage HH10-11, the most used stage for experimental embryology. This analysis is mainly focused on experimental fate mapping results using quail-chick chimeras.This work was supported by Spanish Grants BFU2008-00588, IP from EU LSHG-CT-2004-512003 and INGENIO 2010 MEC-CONSOLIDER CSD 2007-00023. A. Pombero was funded by the Spanish MEC and R. Garcia-Lopez by the European Union Grant: INGENIO 2010 MEC-CONSOLIDER CSD 2007-00023.Peer Reviewe

Developmental mechanisms and experimental models to understand forebrain malformative diseases

The development of the central nervous system can be divided into a number of phases, each of which can be subject of genetic or epigenetic alterations that may originate particular developmental disorders. In recent years, much progress has been made in elucidating the molecular and cellular mechanisms by which the vertebrate forebrain develops. Therefore, our understanding of major developmental brain disorders such as cortical malformations and neuronal migration disorders has significantly increased. In this review, we will describe the major stages in forebrain morphogenesis and regionalization, with special emphasis on developmental molecular mechanisms derailing telencephalic development with subsequent damage to cortical function. Because animal models, mainly mouse, have been fundamental for this progress, we will also describe some characteristic mouse models that have been capital to explore these molecular mechanisms of malformative diseases of the human brain. Although most of the genes involved in the regulation of basic developmental processes are conserved among vertebrates, the extrapolation of mouse data to corresponding gene expression and function in humans needs careful individual analysis in each functional system.This work has been supported by the following grants: LSHG-CT-2004-512003, BFI2002-02979, BFU2005-09085, BFU2005-23722-E/BFI and IP from EU LSHG-CT-2004-512003. C. Vieira is a predoctoral fellow of the Gulbenkian PhD Program in Biomedicine supported by a grant from the Fundaçao para a Ciencia e a Tecnología do Ministerio para a Ciencia e o Encino Superior (FCT/MCES).Peer reviewe

Vascular pattern of the dentate gyrus is regulated by neural progenitors

Neurogenesis is a vital process that begins during early embryonic development and continues until adulthood, though in the latter case, it is restricted to the subventricular zone and the subgranular zone of the dentate gyrus (DG). In particular, the DG's neurogenic properties are structurally and functionally unique, which may be related to its singular vascular pattern. Neurogenesis and angiogenesis share molecular signals and act synergistically, supporting the concept of a neurogenic niche as a functional unit between neural precursors cells and their environment, in which the blood vessels play an important role. Whereas it is well known that vascular development controls neural proliferation in the embryonary and in the adult brain, by releasing neurotrophic factors; the potential influence of neural cells on vascular components during angiogenesis is largely unknown. We have demonstrated that the reduction of neural progenitors leads to a significant impairment of vascular development. Since VEGF is a potential regulator in the neurogenesis-angiogenesis crosstalk, we were interested in assessing the possible role of this molecule in the hippocampal neurovascular development. Our results showed that VEGF is the molecule involved in the regulation of vascular development by neural progenitor cells in the DG.This work was supported by Spanish State Research Agency, through the “Severo Ochoa” Program for Centers of Excellence in R&D (ref. SEV- 2013-0317), by Economy and Competitivity Ministry through Fondos FEDER (SAF2014-59347-C2-1-R), by Generalitat Valenciana Prometeo II Grant (2014/014), by Instituto de Salud Carlos III (RD16/001/0010) (Co-funded by European Regional Development Fund/European Social Fund) and Todos con Natalia Niemann Pick C Association (2016/00084/001).Peer reviewe

Pallial origin of basal forebrain cholinergic neurons in the nucleus basalis of meynert and horizontal limb of the diagonal band nucleus

13 p., 8 figures and references.The majority of the cortical cholinergic innervation implicated in attention and memory originates in the nucleus basalis of Meynert and in the horizontal limb of the diagonal band nucleus of the basal prosencephalon. Functional alterations in this system give rise to neuropsychiatric disorders as well as to the cognitive alterations described in Parkinson and Alzheimer's diseases. Despite the functional importance of these basal forebrain cholinergic neurons very little is known about their origin and development. Previous studies suggest that they originate in the medial ganglionic eminence of the telencephalic subpallium; however, our results identified Tbr1-expressing, reelin-positive neurons migrating from the ventral pallium to the subpallium that differentiate into cholinergic neurons in the basal forebrain nuclei projecting to the cortex. Experiments with Tbr1 knockout mice, which lack ventropallial structures, confirmed the pallial origin of cholinergic neurons in Meynert and horizontal diagonal band nuclei. Also, we demonstrate that Fgf8 signaling in the telencephalic midline attracts these neurons from the pallium to follow a tangential migratory route towards the basal forebrain.This work was supported by DIGESIC-MEC BFU2008-00588, Ingenio 2010 MEC-CONSOLIDER CSD2007-00023, GVA Prometeo 2009/028, ISCIII CIBERSAM, Tercel (RD06/0010/0023) and EU LSHG-CT-2004-512003 (S.M.), and SFB-870 to J.G. A.P. was funded by the grant DIGESIC-MEC BFU2008-00588.Peer reviewe