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Gonzalo P. Solis

Bio: Gonzalo P. Solis is an academic researcher from University of Geneva. The author has contributed to research in topics: Wnt signaling pathway & Neurite. The author has an hindex of 19, co-authored 31 publications receiving 1300 citations. Previous affiliations of Gonzalo P. Solis include University of Konstanz & University of Lausanne.

Papers
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Journal ArticleDOI
TL;DR: Cell-transplantation experiments indicate that the regulation of embryonic cell adhesion by PrP is cell-autonomous, and evolutionarily conserved roles of PrP in cell communication are uncovered, which ultimately impinge on the stability of adherens cell junctions during embryonic development.
Abstract: Prion proteins (PrPs) are key players in fatal neurodegenerative disorders, yet their physiological functions remain unclear, as PrP knockout mice develop rather normally. We report a strong PrP loss-of-function phenotype in zebrafish embryos, characterized by the loss of embryonic cell adhesion and arrested gastrulation. Zebrafish and mouse PrP mRNAs can partially rescue this knockdown phenotype, indicating conserved PrP functions. Using zebrafish, mouse, and Drosophila cells, we show that PrP: (1) mediates Ca+2-independent homophilic cell adhesion and signaling; and (2) modulates Ca+2-dependent cell adhesion by regulating the delivery of E-cadherin to the plasma membrane. In vivo time-lapse analyses reveal that the arrested gastrulation in PrP knockdown embryos is due to deficient morphogenetic cell movements, which rely on E-cadherin–based adhesion. Cell-transplantation experiments indicate that the regulation of embryonic cell adhesion by PrP is cell-autonomous. Moreover, we find that the local accumulation of PrP at cell contact sites is concomitant with the activation of Src-related kinases, the recruitment of reggie/flotillin microdomains, and the reorganization of the actin cytoskeleton, consistent with a role of PrP in the modulation of cell adhesion via signaling. Altogether, our data uncover evolutionarily conserved roles of PrP in cell communication, which ultimately impinge on the stability of adherens cell junctions during embryonic development.

211 citations

Journal ArticleDOI
TL;DR: Reggie-1 and -2 proteins form their own type of non-caveolar membrane microdomains, which are involved in important cellular processes such as T-cell activation, phagocytosis and signalling mediated by the cellular prion protein and insulin; this is consistent with the notion that reggie micro domains promote protein assemblies and signalling.
Abstract: Reggie-1 and -2 proteins (flotillin-2 and -1 respectively) form their own type of non-caveolar membrane microdomains, which are involved in important cellular processes such as T-cell activation, phagocytosis and signalling mediated by the cellular prion protein and insulin; this is consistent with the notion that reggie microdomains promote protein assemblies and signalling. While it is generally known that membrane microdomains contain large multiprotein assemblies, the exact organization of reggie microdomains remains elusive. Using chemical cross-linking approaches, we have demonstrated that reggie complexes are composed of homo- and hetero-tetramers of reggie-1 and -2. Moreover, native reggie oligomers are indeed quite stable, since non-cross-linked tetramers are resistant to 8 M urea treatment. We also show that oligomerization requires the C-terminal but not the N-terminal halves of reggie-1 and -2. Using deletion constructs, we analysed the functional relevance of the three predicted coiled-coil stretches present in the C-terminus of reggie-1. We confirmed experimentally that reggie-1 tetramerization is dependent on the presence of coiled-coil 2 and, partially, of coiled-coil 1. Furthermore, since depletion of reggie-1 by siRNA (small interfering RNA) silencing induces proteasomal degradation of reggie-2, we conclude that the protein stability of reggie-2 depends on the presence of reggie-1. Our data indicate that the basic structural units of reggie microdomains are reggie homo- and hetero-tetramers, which are dependent on the presence of reggie-1.

176 citations

Journal ArticleDOI
TL;DR: In this paper, a major protein component of membrane microdomains, reggie-1/flotillin-2, plays important roles in secretion and spreading of Wnt and Hedgehog in Drosophila.
Abstract: The lipid-modified morphogens Wnt and Hedgehog diffuse poorly in isolation yet can spread over long distances in vivo, predicting existence of two distinct forms of these mophogens. The first is poorly mobile and activates short-range target genes. The second is specifically packed for efficient spreading to induce long-range targets. Subcellular mechanisms involved in the discriminative secretion of these two forms remain elusive. Wnt and Hedgehog can associate with membrane microdomains, but the function of this association was unknown. Here we show that a major protein component of membrane microdomains, reggie-1/flotillin-2, plays important roles in secretion and spreading of Wnt and Hedgehog in Drosophila. Reggie-1 loss-of-function results in reduced spreading of the morphogens, while its overexpression stimulates secretion of Wnt and Hedgehog and expands their diffusion. The resulting changes in the morphogen gradients differently affect the short- and long-range targets. In its action reggie-1 appears specific for Wnt and Hedgehog. These data suggest that reggie-1 is an important component of the Wnt and Hedgehog secretion pathway dedicated to formation of the mobile pool of these morphogens.

110 citations

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TL;DR: It is shown here that reggie‐1/flotillin‐2 microdomains are organized along cortical F‐actin in several cell types and can efficiently be immobilized by actin polymerisation, while exchange of reggie-1/ Flotillin-2 molecules between micro domains is enhanced by actIn disruption as shown by tracking of individual microdomain using TIRF microscopy.

99 citations

Journal ArticleDOI
TL;DR: It is shown that reggies regulate axon regeneration in zebrafish after optic nerve section (ONS) in vivo as well as axon/neurite extension in hippocampal and N2a neurons in vitro through signal transduction molecules modulating actin dynamics.
Abstract: The reggies/flotillins—proteins upregulated during axon regeneration in retinal ganglion cells (RGCs)—are scaffolding proteins of microdomains and involved in neuronal differentiation. Here, we show that reggies regulate axon regeneration in zebrafish (ZF) after optic nerve section (ONS) in vivo as well as axon/neurite extension in hippocampal and N2a neurons in vitro through signal transduction molecules modulating actin dynamics. ZF reggie-1a, -2a, and -2b downregulation by reggie-specific morpholino (Mo) antisense oligonucleotides directly after ONS significantly reduced ZF RGC axon regeneration: RGC axons from reggie Mo retinas were markedly reduced. Moreover, the number of axon-regenerating RGCs, identified by insertion of A488-coupled dextran, decreased by 69% in retinas 7 d after Mo application. At 10 and 14 d, RGCs decreased by 53 and 33%, respectively, in correlation with the gradual inactivation of the Mos. siRNA-mediated knockdown of reggie-1 and -2 inhibited the differentiation and axon/neurite extension in hippocampal and N2a neurons. N2a cells had significantly shorter filopodia, more cells had lamellipodia and fewer neurites, defects which were rescued by a reggie-1 construct without siRNA-binding sites. Furthermore, reggie knockdown strongly perturbed the balanced activation of the Rho family GTPases Rac1, RhoA, and cdc42, influenced the phosphorylation of cortactin and cofilin, the formation of the N-WASP, cortactin and Arp3 complex, and affected p38, Ras, ERK1/2 (extracellular signal-regulated kinases 1 and 2), and focal adhesion kinase activation. Thus, as suggested by their prominent re-expression after lesion, the reggies represent neuron-intrinsic factors for axon outgrowth and regeneration, being crucial for the coordinated assembly of signaling complexes regulating cytoskeletal remodeling.

95 citations


Cited by
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Journal ArticleDOI
TL;DR: Some key aspects of Wnt/beta-catenin signaling in human diseases including congenital malformations, cancer, and osteoporosis are highlighted, and potential therapeutic implications are discussed.

4,926 citations

Journal ArticleDOI
TL;DR: Novel biological insights are revealed into the function of HH lipidation in the secretion and transport of this ligand and details of the signal transduction pathway, which involves Patched 1, Smoothened and GLI proteins, as well as, in vertebrates, primary cilia.
Abstract: The cloning of the founding member of the Hedgehog (HH) family of secreted proteins two decades ago inaugurated a field that has diversified to encompass embryonic development, stem cell biology and tissue homeostasis. Interest in HH signalling increased when the pathway was implicated in several cancers and congenital syndromes. The mechanism of HH signalling is complex and remains incompletely understood. Nevertheless, studies have revealed novel biological insights into this system, including the function of HH lipidation in the secretion and transport of this ligand and details of the signal transduction pathway, which involves Patched 1, Smoothened and GLI proteins (Cubitus interruptus in Drosophila melanogaster), as well as, in vertebrates, primary cilia.

1,437 citations

Journal ArticleDOI
TL;DR: This article reviewed trends in fishmeal and fish oil use in industrial aquafeeds, showing reduced inclusion rates but greater total use associated with increased aquaculture production and demand for fish high in long-chain omega-3 oils.
Abstract: Aquaculture's pressure on forage fisheries remains hotly contested. This article reviews trends in fishmeal and fish oil use in industrial aquafeeds, showing reduced inclusion rates but greater total use associated with increased aquaculture production and demand for fish high in long-chain omega-3 oils. The ratio of wild fisheries inputs to farmed fish output has fallen to 0.63 for the aquaculture sector as a whole but remains as high as 5.0 for Atlantic salmon. Various plant- and animal-based alternatives are now used or available for industrial aquafeeds, depending on relative prices and consumer acceptance, and the outlook for single-cell organisms to replace fish oil is promising. With appropriate economic and regulatory incentives, the transition toward alternative feedstuffs could accelerate, paving the way for a consensus that aquaculture is aiding the ocean, not depleting it.

1,251 citations

Journal ArticleDOI
TL;DR: This review focuses broadly on the current understanding of Hh signaling, from mechanisms of action to cellular and developmental functions, and the role of HH in the pathogenesis of human disease and the possibilities for therapeutic intervention.
Abstract: The Hedgehog (Hh) family of proteins control cell growth, survival, and fate, and pattern almost every aspect of the vertebrate body plan. The use of a single morphogen for such a wide variety of functions is possible because cellular responses to Hh depend on the type of responding cell, the dose of Hh received, and the time cells are exposed to Hh. The Hh gradient is shaped by several proteins that are specifically required for Hh processing, secretion, and transport through tissues. The mechanism of cellular response, in turn, incorporates multiple feedback loops that fine-tune the level of signal sensed by the responding cells. Germline mutations that subtly affect Hh pathway activity are associated with developmental disorders, whereas somatic mutations activating the pathway have been linked to multiple forms of human cancer. This review focuses broadly on our current understanding of Hh signaling, from mechanisms of action to cellular and developmental functions. In addition, we review the role of Hh in the pathogenesis of human disease and the possibilities for therapeutic intervention.

1,163 citations

Journal ArticleDOI
TL;DR: An Aβ oligomer signal transduction pathway that requires PrPC and Fyn to alter synaptic function, with deleterious consequences in Alzheimer's disease is delineated.
Abstract: Amyloid-beta (Aβ) oligomers are thought to trigger Alzheimer's disease pathophysiology. Cellular prion protein (PrP(C)) selectively binds oligomeric Aβ and can mediate Alzheimer's disease-related phenotypes. We examined the specificity, distribution and signaling of Aβ-PrP(C) complexes, seeking to understand how they might alter the function of NMDA receptors (NMDARs) in neurons. PrP(C) is enriched in postsynaptic densities, and Aβ-PrP(C) interaction leads to Fyn kinase activation. Soluble Aβ assemblies derived from the brains of individuals with Alzheimer's disease interacted with PrP(C) to activate Fyn. Aβ engagement of PrP(C)-Fyn signaling yielded phosphorylation of the NR2B subunit of NMDARs, which was coupled to an initial increase and then a loss of surface NMDARs. Aβ-induced dendritic spine loss and lactate dehydrogenase release required both PrP(C) and Fyn, and human familial Alzheimer's disease transgene-induced convulsive seizures did not occur in mice lacking PrP(C). These results delineate an Aβ oligomer signal transduction pathway that requires PrP(C) and Fyn to alter synaptic function, with deleterious consequences in Alzheimer's disease.

573 citations