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Integrin function is regulated by activation involving conformational changes that modulate ligand-binding affinity and downstream signaling. Activation is regulated through inside-out signaling which is controlled by many signaling pathways via a final common pathway through kindlin and talin, which bind to the intracellular tail of beta integrins. Previous studies have shown that the axon growth inhibitory molecules NogoA and chondroitin sulfate proteoglycans (CSPGs) inactivate integrins. Overexpressing kindlin-1 in dorsal root ganglion (DRG) neurons activates integrins, enabling their axons to overcome inhibitory molecules in the environment, and promoting regeneration in vivo following dorsal root crush. Other studies have indicated that expression of the talin head alone or with kindlin can enhance integrin activation. Here, using adult rat DRG neurons, we investigate the effects of overexpressing various forms of talin on axon growth and integrin signaling. We found that overexpression of the talin head activated axonal integrins but inhibited downstream signaling via FAK, and did not promote axon growth. Similarly, co-expression of the talin head and kindlin-1 prevented the growth-promoting effect of kindlin-1, suggesting that the talin head acts as a form of dominant negative for integrin function. Using full-length talin constructs in PC12 cells we observed that neurite growth was enhanced by the expression of wild-type talin and more so by two 'activated' forms of talin produced by point mutation (on laminin and aggrecan-laminin substrates). Nevertheless, co-expression of full-length talin with kindlin did not promote neurite growth more than either molecule alone. In vivo, we find that talin is present in PNS axons (sciatic nerve), and also in CNS axons of the corticospinal tract. ; This work was funded by grants from the Medical Research Council (G1000864), the Henry Smith Charity, the Christopher and Dana Reeve Foundation, the John and Lucille van Geest Foundation, the European Union Framework 7 ...

Retina ganglion cell (RGC) axons grow along a stereotyped pathway undergoing coordinated rounds of fasciculation and defasciculation, which are critical to establishing proper eye– brain connections. How this coordination is achieved is poorly understood, but shedding of guidance cues by metalloproteinases is emerging as a relevant mechanism. Secreted Frizzled Related Proteins (Sfrps) are multifunctional proteins, which, among others, reorient RGC growth cones by regulating intracellular second messengers, and interact with Tolloid and ADAM metalloproteinases, thereby repressing their activity. Here, we show that the combination of these two functions well explain the axon guidance phenotype observed in Sfrp1 and Sfrp2 single and compound mouse mutant embryos, in whichRGCaxons make subtle but significant mistakes during their intraretinal growth and inappropriately defasciculate along their pathway. The distribution of Sfrp1 and Sfrp2 in the eye is consistent with the idea that Sfrp1/2 normally constrain axon growth into the fiber layer and the optic disc. Disheveled axon growth instead seems linked to Sfrp-mediated modulation of metalloproteinase activity. Indeed, retinal explants from embryos with different Sfrp-null alleles or explants overexpressing ADAM10 extend axons with a disheveled appearance, which is reverted by the addition of Sfrp1 or an ADAM10-specific inhibitor. This mode of growth is associated with an abnormal proteolytic processing of L1 and N-cadherin, two ADAM10 substrates previously implicated in axon guidance.Wethus propose that Sfrps contribute to coordinate visual axon growth with a dual mechanism: by directly signaling at the growth cone and by regulating the processing of other relevant cues ; This work was supported by the Spanish MINECO (Grants BFU2010-16031 and BFU2013-43213-P), Comunidad Autónoma de Madrid (Grant S2010/BMD-2315) Cost Action BM1001 Brain ECM in Health and Disease, an institutional grant from the Fundación Ramón Areces and Centro de Investigación Biomédica en Red de Enfermedades Raras (P.B.). F.N.-L. and M.J.C. were supported by a FPU and FPI fellowship from the Spanish Government, respectively. We thank F. Murakami, L. Erskine, A. Chedotal, A. Ludwig, and V.P. Lemmon for reagents

Retina ganglion cell (RGC) axons grow along a stereotyped pathway undergoing coordinated rounds of fasciculation and defasciculation, which are critical to establishing proper eye– brain connections. How this coordination is achieved is poorly understood, but shedding of guidance cues by metalloproteinases is emerging as a relevant mechanism. Secreted Frizzled Related Proteins (Sfrps) are multifunctional proteins, which, among others, reorient RGC growth cones by regulating intracellular second messengers, and interact with Tolloid and ADAM metalloproteinases, thereby repressing their activity. Here, we show that the combination of these two functions well explain the axon guidance phenotype observed in Sfrp1 and Sfrp2 single and compound mouse mutant embryos, in whichRGCaxons make subtle but significant mistakes during their intraretinal growth and inappropriately defasciculate along their pathway. The distribution of Sfrp1 and Sfrp2 in the eye is consistent with the idea that Sfrp1/2 normally constrain axon growth into the fiber layer and the optic disc. Disheveled axon growth instead seems linked to Sfrp-mediated modulation of metalloproteinase activity. Indeed, retinal explants from embryos with different Sfrp-null alleles or explants overexpressing ADAM10 extend axons with a disheveled appearance, which is reverted by the addition of Sfrp1 or an ADAM10-specific inhibitor. This mode of growth is associated with an abnormal proteolytic processing of L1 and N-cadherin, two ADAM10 substrates previously implicated in axon guidance.Wethus propose that Sfrps contribute to coordinate visual axon growth with a dual mechanism: by directly signaling at the growth cone and by regulating the processing of other relevant cues. ; This work was supported by the Spanish MINECO (Grants BFU2010-16031 and BFU2013-43213-P), Comunidad Autonoma de Madrid (Grant S2010/BMD-2315) Cost Action BM1001 Brain ECM in Health and Disease, an institutional grant from the Fundación Ramón Areces and Centro de Investigación Biomédica en Red de Enfermedades Raras (P.B.). F.N.-L. and M.J.C. were supported by a FPU and FPI fellowship from the Spanish Government, respectively. ; Peer Reviewed

Frontiers in Cellular Neuroscience OCT (2013): 197 this Document is Protected by copyright and was first published by Frontiers. All rights reserved. It is reproduced with permission ; Brain development requires the interaction of complex signaling pathways, involving different cell types and molecules. For a long time, most attention has focused on neurons in a neuronocentric conceptualization of central nervous system development, these cells fulfilling an intrinsic program that establishes the brain's morphology and function. By contrast, glia have mainly been studied as support cells, offering guidance or as the cells that react to brain injury. However, new evidence is appearing that demonstrates a more fundamental role of glial cells in the control of different aspects of neuronal development and function, events in which the influence of neurons is at best weak. Moreover, it is becoming clear that the function and organization of the nervous system depends heavily on reciprocal neuron-glia interactions. During development, neurons are often generated far from their final destination and while intrinsic mechanisms are responsible for neuronal migration and growth, they need support and regulatory influences from glial cells in order to migrate correctly. Similarly, the axons emitted by neurons often have to reach faraway targets and in this sense, glia help define the way that axons grow. Moreover, oligodendrocytes and Schwann cells ultimately envelop axons, contributing to the generation of nodes of Ranvier. Finally, recent publications show that astrocytes contribute to the modulation of synaptic transmission. In this sense, purinergic receptors are expressed widely by glial cells and neurons, and recent evidence points to multiple roles of purines and purinergic receptors in neuronal development and function, from neurogenesis to axon growth and functional axonal maturation, as well as in pathological conditions in the brain. This review will focus on the role of glial and neuronal secreted purines, and on the purinergic receptors, fundamentally in the control of neuronal development and function, as well as in diseases of the nervous system ; This work was supported by GrantsSAF2009-12249-C02-02, SAF2012-39148-C03-03, and SAF2012-39148-C03-01 from the Spanish Government

Cultured neurons obtained from a hypomorphous MAP1B mutant mouse line display a selective and significant inhibition of axon formation that reflects a delay in axon outgrowth and a reduced rate of elongation. This phenomenon is paralleled by decreased microtubule formation and dynamics, which is dramatic at the distal axonal segment, as well as in growth cones, where the more recently assembled microtubule polymer normally predominates. These neurons also have aberrant growth cone formation and increased actin-based protrusive activity. Taken together, this study provides direct evidence showing that by promoting microtubule dynamics and regulating cytoskeletal organization MAP1B has a crucial role in axon formation. ; This work was supported by grants from the Spanish Direccion General de Investigacion Cientifica y Tecnica, Comunidad de Madrid, European Union, and an institutional grant from Formation de Recherche Associee to J.A. It was also supported by grants from Consejo Nacional de Investigaciones Cientificas y Tecnicas de Argentina (PICT-PIP 4906), FONCyT (PICT 05-00000-00937 and 99-5-6179), CONICOR, and a Howard Hughes Medical Institute Grant (HMMI 75197-553201) awarded under the International Research Scholars Program to A.C. An A.E.C.I./I.C.I. predoctoral fellowship was awarded to C.G.-B. The MAP1B mutant mouse was generated with financial support from Amgen and the Max Planck Society in the laboratory of Prof. P. Gruss. ; Peer reviewed

APRIL (A Proliferation-Inducing Ligand, TNFSF13) is a member of the tumor necrosis factor superfamily that regulates lymphocyte survival and activation and has been implicated in tumorigenesis and autoimmune diseases. Here we report the expression and first known activity of APRIL in the nervous system. APRIL and one of its receptors, BCMA (B-Cell Maturation Antigen, TNFRSF17), are expressed by hippocampal pyramidal cells of fetal and postnatal mice. In culture, these neurons secreted APRIL, and function-blocking antibodies to either APRIL or BCMA reduced axonal elongation. Recombinant APRIL enhanced axonal elongation, but did not influence dendrite elongation. The effect of APRIL on axon elongation was inhibited by anti-BCMA and the expression of a signaling-defective BCMA mutant in these neurons, suggesting that the axon growth-promoting effect of APRIL is mediated by BCMA. APRIL promoted phosphorylation and activation of ERK1, ERK2 and Akt and serine phosphorylation and inactivation of GSK-3β in cultured hippocampal pyramidal cells. Inhibition of MEK1/MEK2 (activators of ERK1/ERK2), PI3-kinase (activator of Akt) or Akt inhibited the axon growth-promoting action of APRIL, as did pharmacological activation of GSK-3β and the expression of a constitutively active form of GSK-3β. These findings suggest that APRIL promotes axon elongation by a mechanism that depends both on ERK signaling and PI3-kinase/Akt/GSK-3β signaling ; This work was supported by the Wellcome Trust (grant number 085984) to AMD and Proyecto de Excelencia of the Regional Government of Andalussia (grant number P10-CVI-6740) to AR. CO was a recipient of Fundacao para a Ciencia e a Tecnologia PhD grant. PC was a recipient of a 'Sara Borrell' Postdoctoral Fellowship from the National Institute of Health 'Carlos III', Spain (grant number CD08/ 00078). ; Peer Reviewed

Abstract
Dentate granule cells (GCs) have been characterized as unilaterally projecting neurons within each hippocampus. Here, we describe a unique class, the commissural GCs, which atypically project to the contralateral hippocampus in mice. Although commissural GCs are rare in the healthy brain, their number and contralateral axon density rapidly increase in a rodent model of temporal lobe epilepsies. In this model, commissural GC axon growth appears together with the well-studied hippocampal mossy fiber sprouting and may be important for the pathomechanisms of epilepsy. Our results augment the current view on hippocampal GC diversity and demonstrate powerful activation of a commissural wiring program in the adult brain.

Brain development requires the interaction of complex signaling pathways, involving different cell types and molecules. For a long time, most attention has focused on neurons in a neuronocentric conceptualization of central nervous system development, these cells fulfilling an intrinsic program that establishes the brain's morphology and function. By contrast, glia have mainly been studied as support cells, offering guidance or as the cells that react to brain injury. However, new evidence is appearing that demonstrates a more fundamental role of glial cells in the control of different aspects of neuronal development and function, events in which the influence of neurons is at best weak. Moreover, it is becoming clear that the function and organization of the nervous system depends heavily on reciprocal neuron-glia interactions. During development, neurons are often generated far from their final destination and while intrinsic mechanisms are responsible for neuronal migration and growth, they need support and regulatory influences from glial cells in order to migrate correctly. Similarly, the axons emitted by neurons often have to reach faraway targets and in this sense, glia help define the way that axons grow. Moreover, oligodendrocytes and Schwann cells ultimately envelop axons, contributing to the generation of nodes of Ranvier. Finally, recent publications show that astrocytes contribute to the modulation of synaptic transmission. In this sense, purinergic receptors are expressed widely by glial cells and neurons, and recent evidence points to multiple roles of purines and purinergic receptors in neuronal development and function, from neurogenesis to axon growth and functional axonal maturation, as well as in pathological conditions in the brain. This review will focus on the role of glial and neuronal secreted purines, and on the purinergic receptors, fundamentally in the control of neuronal development and function, as well as in diseases of the nervous system. © 2013 del Puerto, Wandosell and Garrido. ; Spanish Government (SAF2009-12249-C02-02, SAF2012-39148-C03-03, SAF2012-39148-C03-01) ; Peer Reviewed

Intro -- United Arab Emirates 1975/76-2018 -- Copyright -- Contents -- Preface -- Acronyms -- Map -- Introduction -- 1975/76 -- Diplomatic Troubles - Federal Cabinet - Abu Dhabi and Dubai, Rivals United? - Oil, 100 per cent Nationalisation - Development Spending - Port Zayed - Port Rashid -- 1977 -- Constitution - Supreme Council - Aid Programme - Qawasimi Legacy - Industrialisation - Jebel Ali Plans - Currency Board - One Market? -- 1978 -- Minor Hiccoughs - Federalisation - UAE Mediation in Gulf war - Banks Galore Competitive Rivalry - Capital Expenditure Reduced - ADNOC Dominance - Taweelah - Renewed Investment Confidence -- 1979 -- Rumours of Discontent - Provisional Constitution - Secession? - Metres, not Kilometres - Sharjah's Status - OPEC Alignments - Omani Discontent - Common Economic Trends - Dirham Revalued - TEPCO - Social Infrastructure - Recession - Gas Engineering Concerns - Banking Reforms - Agriculture's Future -- 1980 -- Government Crisis - Abu Dhabi-Dubai Rivalry - Questioning the Sheikhly System - Currency Board - Ruwais - GASCO - Das Island Disappointment - Industry - Economic Slowdown -- 1981 -- Cabinet Reshuffle - Economic Imbalance - UAE University - Hospital Growth - Desalination - Business, not Boom - Dubai: Efficiency and Profit - Over-banking -- 1982 -- Federation, not Unity - Imbalance, Over-dependence on Oil - After-effects of Construction Boom - Economics Override Politics - Hospitals, and a University - Economic Duplication - Abu Dhabi Calls the Shots - Dubai's Mercantile Expertise - Stately Sharjah - Rocky Ras al-Khaimah - Ajman's Marbles - Umm al-Quwain: More than a Dormitory - Fujairah: Natural Advantages -- 1983 -- Memorandum Movement - Five-Year Plan 1981-85 - Gulf Co-operation Council (GCC) - Sharjah-Dubai Border Dispute - Economic Re-thinking - OPEC - Budget Deficit - Tourism -- 1984.

13 páginas, 9 figuras.-- et al. ; Vav3 is a phosphorylation-dependent activator of Rho/Rac GTPases that has been implicated in hematopoietic, bone, cerebellar, and cardiovascular roles. Consistent with the latter function, Vav3-deficient mice develop hypertension, tachycardia, and renocardiovascular dysfunctions. The cause of those defects remains unknown as yet. Here, we show that Vav3 is expressed in GABAegic neurons of the ventrolateral medulla (VLM), a brainstem area that modulates respiratory rates and, via sympathetic efferents, a large number of physiological circuits controlling blood pressure. On Vav3 loss, GABAergic cells of the caudal VLM cannot innervate properly their postsynaptic targets in the rostral VLM, leading to reduced GABAergic transmission between these two areas. This results in an abnormal regulation of catecholamine blood levels and in improper control of blood pressure and respiration rates to GABAergic signals. By contrast, the reaction of the rostral VLM to excitatory signals is not impaired. Consistent with those observations, we also demonstrate that Vav3 plays important roles in axon branching and growth cone morphology in primary GABAergic cells. Our study discloses an essential and nonredundant role for this Vav family member in axon guidance events in brainstem neurons that control blood pressure and respiratory rates. ; X.R.B. is supported by the National Institutes of Health (R01CA073735), the Spanish Ministry of Science and Innovation (SMSI, SAF2009-07172, and RD06/0020/0001), the Castilla y León Autonomous Government (GR97), and the Asociacion Española contra el Cancer. B.R. is supported by SMSI (SAF2007-61904 and CSD2007-00023) and "La Caixa" Foundation grants. ; Peer reviewed

Abstract
Drosophila Down syndrome cell adhesion molecule 1 (Dscam1) encodes tens of thousands of cell recognition molecules via alternative splicing, which are required for neural function. A canonical self-avoidance model seems to provide a central mechanistic basis for Dscam1 functions in neuronal wiring. Here, we reveal extensive noncanonical functions of Dscam1 isoforms in neuronal wiring. We generated a series of allelic cis mutations in Dscam1, encoding a normal number of isoforms, but with an altered isoform composition. Despite normal dendritic self-avoidance and self-/nonself-discrimination in dendritic arborization (da) neurons, which is consistent with the canonical self-avoidance model, these mutants exhibited strikingly distinct spectra of phenotypic defects in the three types of neurons: up to ∼60% defects in mushroom bodies, a significant increase in branching and growth in da neurons, and mild axonal branching defects in mechanosensory neurons. Remarkably, the altered isoform composition resulted in increased dendrite growth yet inhibited axon growth. Moreover, reducing Dscam1 dosage exacerbated axonal defects in mushroom bodies and mechanosensory neurons but reverted dendritic branching and growth defects in da neurons. This splicing-tuned regulation strategy suggests that axon and dendrite growth in diverse neurons cell-autonomously require Dscam1 isoform composition. These findings provide important insights into the functions of Dscam1 isoforms in neuronal wiring.

During primary infection, herpes simplex virus 2 (HSV-2) replicates in epithelial cells and enters neurites to infect neurons of the peripheral nervous system. Growth factors and attractive and repulsive directional cues influence neurite outgrowth and neuronal survival. We hypothesized that HSV-2 modulates the activity of such cues to increase neurite outgrowth. To test this hypothesis, we exposed sensory neurons to nerve growth factor (NGF) and mock- or HSV-2-infected HEK- 293T cells, since they express repellents of neurite outgrowth. We show that HEK- 293T cells secrete factors that inhibit neurite outgrowth, while infection with HSV-2 strains MS and 333 reduces this repelling phenotype, increasing neurite numbers. The HSV-2-mediated restoration of neurite outgrowth required the activity of NGF. In the absence of infection, however, NGF did not overcome the repulsion mediated by HEK-293T cells. We previously showed that recombinant, soluble glycoprotein G of HSV-2 (rSgG2) binds and enhances NGF activity, increasing neurite outgrowth. However, the effect of gG2 during infection has not been investigated. Therefore, we addressed whether gG2 contributes to overcoming neurite outgrowth repulsion. To do so, we generated viruses lacking gG2 expression and complemented them by exogenous expression of gG2. Overall, our results suggest that HSV-2 infection of nonneuronal cells reduces their repelling effect on neurite outgrowth in an NGF-dependent manner. gG2 contributed to this phenotype, but it was not the only factor. The enhanced neurite outgrowth may facilitate HSV-2 spread from epithelial cells into neurons expressing NGF receptors and increase HSV-2-mediated pathogenesis. ; Deutsche Forschungsgemeinschaft (DFG [German Research Foundation]) grant SFB 900/3-158989968 to A.V.-B. (TPB9) and B.S. (TPC2) (https://www.mh-hannover.de/sfb900.html) and by the DFG under Germany's Excellence Strategy (grant EXC 2155, project number 390874280, to B.S. and A.V.-B. and Cluster of Excellence REBIRTH to B.S. [Unit 8.1]). A.V.-B. received a Marie Curie Career Integration Grant fellowship (European Union Horizon 2020 program FP7-PEOPLE-2013-CIG [INMA] project number 631792), and K.A.K. was funded by grant SFB 900/3 from the DFG. S.S. was funded by the Niedersachsen-Research Network on Neuroinfectiology (N-RENNT) of the Ministry of Science and Culture of Lower Saxony (to B.S. and A.V.-B.; http://www.tiho-hannover.de/forschung/n-rennt/). J.S.C. was funded by the Free and Hanseatic City of Hamburg, Germany (grant Graduiertenkolleg DELIGRAH LFFGK06). A.D. was funded by core funding from the Hannover Medical School. The laboratory of A.A. was funded by the Spanish Ministry of Economy and Competitiveness and the European Union (European Regional Development Funds [FEDER] grant SAF2015-67485-R), and A.D.L.-M. was funded by a Ph.D. fellowship from the Ministerio de Educacion, Cultura y Deporte

Abstract We examine if resource revenues are likely to be managed more effectively with strong (or lack of) institutions and if so to contribute to economic development in resource abundant countries. We estimate a general model using evidence for the resource booms of the 1970-2012 period, resource rents, natural capital, socio-economic indicators and for institutions. Results show on the one hand 1) countries with ample natural capital and subsoil wealth levels are associated to a healthier democracy which potentially mitigates the resource curse; while on the other 2) high resource rents are negatively associated to weak institutional quality deepening the curse. Long run economic growth is positively associated to natural capital but negatively associated for those countries that receive high resource rents. We recommend stronger transparency for revenue allocation, for sales of oil production, for the allocation of licences, and for revenue collection. One limitation is the lack of information: (energy) laws inducing economic growth. This paper contributes to explaining the long run impact of democratic change on managing resource revenue.

Dendrite size and morphology are key determinants of the functional properties of neurons. Here, we show that growth differentiation factor 5 (GDF5), a member of the bone morphogenetic protein (BMP) subclass of the transforming growth factor β superfamily with a wellcharacterised role in limb morphogenesis, is a key regulator of the growth and elaboration of pyramidal cell dendrites in the developing hippocampus. Pyramidal cells co-express GDF5 and its preferred receptors, BMP receptor 1B and BMP receptor 2, during development. In culture, GDF5 substantially increased dendrite, but not axon, elongation from these neurons by a mechanism that depends on activation of SMADs 1/5/8 and upregulation of the transcription factor HES5. In vivo, the apical and basal dendritic arbours of pyramidal cells throughout the hippocampus were markedly stunted in both homozygous and heterozygous Gdf5 null mutants, indicating that dendrite size and complexity are exquisitely sensitive to the level of endogenous GDF5 synthesis. © 2013. ; This work was supported by the Wellcome Trust [grant number 085984 to A.M.D.]; Proyecto de Excelencia of Regional Government Andalussia [grant number P10- CVI-6740 to A.R.-T.]; Fundação para a Ciencia e a Tecnologia [grant SFRH/BD/60498/2009 to C.O.]; and a 'Sara Borrell' Postdoctoral Fellowship from the National Institutes of Health 'Carlos III', Spain [grant number CD08/00078 to P.J.C.]. Deposited in PMC for immediate release ; Peer Reviewed