Bio

Honors & Awards


  • American Heart Association postdoctoral fellowship, American Heart Association (2012-2014)
  • Pew Latin American Fellowship, The Pew Latin American Fellows Program in the Biomedical Sciences (2010-2012)
  • Becas Chile Fellowship, National Commission for Research, Science and Technology (CONICYT) (2010-2012)
  • Development Traveling Fellowships, The Company of Biologists (2005)
  • Graduate Student Fellowship, National Commission for Research, Science and Technology (CONICYT) (2003-2007)

Professional Education


  • Doctor of Philosophy, Pont Universidad Catolica De Chile (2007)

Stanford Advisors


Research & Scholarship

Current Research and Scholarly Interests


Stem cells are unique in that can renew themselves through cell division or differentiate into a diverse range of specialized cell types. I will study genes that functions to prevent the growth of tumors and regulates stem cell decisions. Understanding the molecular mechanisms that mediate the choice between self-renewal and differentiation in stem cells has important implications for many areas of biology, including ancer treatment, regenerative medicine and new cell-based therapies.

Publications

Journal Articles


  • A Self-Limiting Switch Based on Translational Control Regulates the Transition from Proliferation to Differentiation in an Adult Stem Cell Lineage CELL STEM CELL Insco, M. L., Bailey, A. S., Kim, J., Olivares, G. H., Wapinski, O. L., Tam, C. H., Fuller, M. T. 2012; 11 (5): 689-700

    Abstract

    In adult stem cell lineages, progenitor cells commonly undergo mitotic transit amplifying (TA) divisions before terminal differentiation, allowing production of many differentiated progeny per stem cell division. Mechanisms that limit TA divisions and trigger the switch to differentiation may protect against cancer by preventing accumulation of oncogenic mutations in the proliferating population. Here we show that the switch from TA proliferation to differentiation in the Drosophila male germline stem cell lineage is mediated by translational control. The TRIM-NHL tumor suppressor homolog Mei-P26 facilitates accumulation of the differentiation regulator Bam in TA cells. In turn, Bam and its partner Bgcn bind the mei-P26 3' untranslated region and repress translation of mei-P26 in late TA cells. Thus, germ cells progress through distinct, sequential regulatory states, from Mei-P26 on/Bam off to Bam on/Mei-P26 off. TRIM-NHL homologs across species facilitate the switch from proliferation to differentiation, suggesting a conserved developmentally programmed tumor suppressor mechanism.

    View details for DOI 10.1016/j.stem.2012.08.012

    View details for Web of Science ID 000311471900014

    View details for PubMedID 23122292

  • Expression of Transposable Elements in Neural Tissues during Xenopus Development PLOS ONE Faunes, F., Sanchez, N., Moreno, M., Olivares, G. H., Lee-Liu, D., Almonacid, L., Slater, A. W., Norambuena, T., Taft, R. J., Mattick, J. S., Melo, F., Larrain, J. 2011; 6 (7)

    Abstract

    Transposable elements comprise a large proportion of animal genomes. Transposons can have detrimental effects on genome stability but also offer positive roles for genome evolution and gene expression regulation. Proper balance of the positive and deleterious effects of transposons is crucial for cell homeostasis and requires a mechanism that tightly regulates their expression. Herein we describe the expression of DNA transposons of the Tc1/mariner superfamily during Xenopus development. Sense and antisense transcripts containing complete Tc1-2_Xt were detected in Xenopus embryos. Both transcripts were found in zygotic stages and were mainly localized in Spemann's organizer and neural tissues. In addition, the Tc1-like elements Eagle, Froggy, Jumpy, Maya, Xeminos and TXr were also expressed in zygotic stages but not oocytes in X. tropicalis. Interestingly, although Tc1-2_Xt transcripts were not detected in Xenopus laevis embryos, transcripts from other two Tc1-like elements (TXr and TXz) presented a similar temporal and spatial pattern during X. laevis development. Deep sequencing analysis of Xenopus tropicalis gastrulae showed that PIWI-interacting RNAs (piRNAs) are specifically derived from several Tc1-like elements. The localized expression of Tc1-like elements in neural tissues suggests that they could play a role during the development of the Xenopus nervous system.

    View details for DOI 10.1371/journal.pone.0022569

    View details for Web of Science ID 000293175100033

    View details for PubMedID 21818339

  • SHh activity and localization is regulated by perlecan BIOLOGICAL RESEARCH Palma, V., Carrasco, H., Reinchisi, G., Olivares, G., Faunes, F., Larrain, J. 2011; 44 (1): 63-67

    Abstract

    Proliferation and cell fate determination in the developing embryo are extrinsically regulated by multiple interactions among diverse secreted factors, such as Sonic Hedgehog (SHh), which act in a concentration-dependent manner. The fact that SHh is secreted as a lipid-modified protein suggests the existence of a mechanism to regulate its movement across embryonic fields. We have previously shown that heparan sulfate proteoglycans (HSPGs) are required for SHh binding and signalling. However, it was not determined which specific HSPG was responsible for these functions. Here we evaluated the contribution of perlecan on SHh localization and activity. To understand the mechanism of action of perlecan at the cellular level, we studied the role of perlecan-SHh interaction in SHh activity using both cell culture and biochemical assays. Our findings show that perlecan is a crucial anchor and modulator of SHh activity acting as an extracellular positive regulator of SHh.

    View details for Web of Science ID 000289541700008

    View details for PubMedID 21720682

  • Non-canonical Wnt Signaling Induces Ubiquitination and Degradation of Syndecan JOURNAL OF BIOLOGICAL CHEMISTRY Carvallo, L., Munoz, R., Bustos, F., Escobedo, N., Carrasco, H., Olivares, G., Larrain, J. 2010; 285 (38): 29546-29555

    Abstract

    Dynamic regulation of cell adhesion receptors is required for proper cell migration in embryogenesis, tissue repair, and cancer. Integrins and Syndecan4 (SDC4) are the main cell adhesion receptors involved in focal adhesion formation and are required for cell migration. SDC4 interacts biochemically and functionally with components of the Wnt pathway such as Frizzled7 and Dishevelled. Non-canonical Wnt signaling, particularly components of the planar cell polarity branch, controls cell adhesion and migration in embryogenesis and metastatic events. Here, we evaluate the effect of this pathway on SDC4. We have found that Wnt5a reduces cell surface levels and promotes ubiquitination and degradation of SDC4 in cell lines and dorsal mesodermal cells from Xenopus gastrulae. Gain- and loss-of-function experiments demonstrate that Dsh plays a key role in regulating SDC4 steady-state levels. Moreover, a SDC4 deletion construct that interacts inefficiently with Dsh is resistant to Wnt5a-induced degradation. Non-canonical Wnt signaling promotes monoubiquitination of the variable region of SDC4 cytoplasmic domain. Mutation of these specific residues abrogates ubiquitination and results in increased SDC4 steady-state levels. This is the first example of a cell surface protein ubiquitinated and degraded in a Wnt/Dsh-dependent manner.

    View details for DOI 10.1074/jbc.M110.155812

    View details for Web of Science ID 000281740100056

    View details for PubMedID 20639201

  • Syndecan-1 regulates BMP signaling and dorso-ventral patterning of the ectoderm during early Xenopus development DEVELOPMENTAL BIOLOGY Olivares, G. H., Carrasco, H., Aroca, F., Carvallo, L., Segovia, F., Larrain, J. 2009; 329 (2): 338-349

    Abstract

    Extracellular regulation of growth factor signaling is a key event for embryonic patterning. Heparan sulfate proteoglycans (HSPG) are among the molecules that regulate this signaling during embryonic development. Here we study the function of syndecan1 (Syn1), a cell-surface HSPG expressed in the non-neural ectoderm during early development of Xenopus embryos. Overexpression of Xenopus Syn1 (xSyn1) mRNA is sufficient to reduce BMP signaling, induce chordin expression and rescue dorso-ventral patterning in ventralized embryos. Experiments using chordin morpholinos established that xSyn1 mRNA can inhibit BMP signaling in the absence of chordin. Knockdown of xSyn1 resulted in a reduction of BMP signaling and expansion of the neural plate with the concomitant reduction of the non-neural ectoderm. Overexpression of xSyn1 mRNA in xSyn1 morphant embryos resulted in a biphasic effect, with BMP being inhibited at high concentrations and activated at low concentrations of xSyn1. Interestingly, the function of xSyn1 on dorso-ventral patterning and BMP signaling is specific for this HSPG. In summary, we report that xSyn1 regulates dorso-ventral patterning of the ectoderm through modulation of BMP signaling.

    View details for DOI 10.1016/j.ydbio.2009.03.007

    View details for Web of Science ID 000266048300015

    View details for PubMedID 19303002

  • Heparan sulfate proteoglycans exert positive and negative effects in Shh activity JOURNAL OF CELLULAR BIOCHEMISTRY Carrasco, H., Olivares, G. H., Faunes, F., Oliva, C., Larrain, J. 2005; 96 (4): 831-838

    Abstract

    Hedgehog (Hh) proteins are morphogens involved in short- and long-range effects during early embryonic development. Genetic analysis in fly and vertebrate embryos showed that heparan sulfate proteoglycans (HSPGs) are required for Hh transport and signaling. To further understand how HSPGs regulate Sonic hedgehog (Shh), we performed experiments using cell culture and biochemical assays. When the synthesis of HSPGs was reduced, a decrease in Shh activity was observed. Contrary to that, addition of a peptide that competes the binding of Shh to HSPGs resulted in augmentation of Shh activity. From these results, we concluded that HSPGs exert positive and negative effects in Shh activity. This dual effect correlates with the finding that Shh interacts preferentially with two HSPGs. The current model for the role of HSPGs in Shh diffusion is discussed in view of our findings.

    View details for DOI 10.1002/jcb.20586

    View details for Web of Science ID 000232857000017

    View details for PubMedID 16149075

  • Trolox and 17 beta-estradiol protect against amyloid beta-peptide neurotoxicity by a mechanism that involves modulation of the Wnt signaling pathway JOURNAL OF BIOLOGICAL CHEMISTRY Quintanilla, R. A., Munoz, F. J., Metcalfe, M. J., HITSCHFELD, M., Olivares, G., Godoy, J. A., Inestrosa, N. C. 2005; 280 (12): 11615-11625

    Abstract

    Oxidative stress is a key mechanism in amyloid beta-peptide (A beta)-mediated neurotoxicity; therefore, the protective roles of 17beta-estradiol (E2) and antioxidants (Trolox and vitamin C) were assayed on hippocampal neurons. Our results show the following: 1) E2 and Trolox attenuated the neurotoxicity mediated by A beta and H2O2 as measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction assays, quantification of apoptotic cells, and morphological studies of the integrity of the neurite network. 2) Vitamin C failed to protect neurons from A beta toxicity. 3) A beta-mediated endoperoxide production, reported to induce cell damage, was decreased in the presence of E2 and Trolox. 4) Two key Wnt signaling components were affected by E2 and Trolox; in fact, the enzyme glycogen synthase kinase 3beta was inhibited by both E2 and Trolox, and both compounds were able to stabilize cytoplasmic beta-catenin. 5) E2 activated the expression of the Wnt-5a and Wnt-7a ligands, and at the same time, E2, through the alpha-estrogen receptor, was able to prevent the excitotoxic A beta-induced rise in bulk-free Ca2+ as an alternative pathway to increase cell viability. 6) Finally, the Wnt-7a ligand protected against cytoplasmic calcium disturbances induced by A beta treatment. Our results suggest that control of oxidative stress, regulation of cytoplasmic calcium, and activation of Wnt signaling may prevent A beta neurotoxicity.

    View details for DOI 10.1074/jbc.M411936200

    View details for Web of Science ID 000227761800089

    View details for PubMedID 15659394

  • Wnt-3a overcomes beta-amyloid toxicity in rat hippocampal neurons EXPERIMENTAL CELL RESEARCH Alvarez, A. R., Godoy, J. A., Mullendorff, K., Olivares, G. H., Bronfman, M., Inestrosa, N. C. 2004; 297 (1): 186-196

    Abstract

    The aim of this study was to evaluate whether the direct activation of the Wnt signaling pathway by its endogenous Wnt-3a ligand prevents the toxic effects induced by amyloid-beta-peptide (Abeta) in rat hippocampal neurons. We report herein that the Wnt-3a ligand was indeed able to overcome toxic effects induced by Abeta in hippocampal neurons, including a neuronal impairment on cell survival, an increase in glycogen synthase kinase-3beta (GSK-3beta) and tau phosphorylation, a decrease in cytoplasmic beta-catenin and a decrease in the expression of the Wnt target gene engrailed-1. We further demonstrate that Wnt-3a protects hippocampal neurons from apoptosis induced by Abeta. Our results support the hypothesis that a loss of function of Wnt signaling may play a role in the progression of neurodegenerative diseases such as Alzheimer's disease.

    View details for DOI 10.1016/j.yexer.2004.02.028

    View details for Web of Science ID 000222174400016

    View details for PubMedID 15194435

  • Wnt signaling involvement in beta-amyloid-dependent neurodegeneration NEUROCHEMISTRY INTERNATIONAL Inestrosa, N. C., De Ferrari, G. V., Garrido, J. L., Alvarez, A., Olivares, G. H., Barria, M. I., Bronfman, M., Chacon, M. A. 2002; 41 (5): 341-344

    Abstract

    Alzheimer's disease (AD) is a progressive dementia paralleled by selective neuronal death, which is probably caused by the cytotoxic effects of the amyloid-beta peptide (Abeta). We have observed that Abeta-dependent neurotoxicity induces a loss of function of Wnt signaling components and that activation of this signaling cascade prevent such cytotoxic effects. Therefore we propose that compounds which mimic this signaling cascade may be candidates for therapeutic intervention in Alzheimer's patients.

    View details for Web of Science ID 000178161300009

    View details for PubMedID 12176076

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