Bio

Bio


For the past 20 years I have studied the biology of the urochordate Botryllus schlosseri and contributed to its development as a model organism for the study of stem cell biology, immunology and evolution. As a postdoctoral fellow in Irv Weissman?s lab. at Stanford, I identified and isolated the first adult stem cell (Cell Stem Cell, 2008) and the first germline stem cell niche in B. schlosseri (Dev. Cell, 2013). I also discovered that B. schlosseri exhibits an alternative regeneration pathway whereby whole body regeneration occurs from the vasculature alone: a process in which a normal colony of individuals is regenerated through multiple generations of abnormal intermediate forms that gradually converge into an individual with normal physiology and morphology (FASEB J., 2007). Since 2010, I have been directing and conducting the B. schlosseri genome project, a project that has involved 19 scientists in bioinformatics and molecular and cell biology from Irv Weissman?s and Stephen Quake?s labs and several international laboratories. Using our novel method for high-throughput sequencing of repeat-rich genomes (called LRseq; acquired by Illumina), we sequenced and assembled the 580-Mbp of the B. schlosseri genome. The B. schlosseri genome revealed critical events underlying the early evolution of vertebrates, including the first known appearance of genes related to hematopoiesis, cardiac, optic and auditory development (Elife, 2013). Using this newly sequenced B. schlosseri genome, we looked carefully into a single polymorphic gene locus that governs fusion/rejection outcomes in B. schlosseri colonies. This locus, called Fu/HC for fusion/histocompatibility, encodes multiple co-dominant alleles in natural populations, and progeny from crosses between histocompatible colonies are known to segregate in a manner consistent with a monogenetic trait. Using genetically Fu/HC defined lines, whole-transcriptome sequencing of 23 colonies, and a novel genomics approach, we identified BHF, the gene that encodes self and determines ?graft? outcomes in this organism. Our genome-wide study revealed the first fusion-rejection system understood to the point where one can reliably predict, based on a single gene, the outcome of histocompatibility reactions. These findings establish an experimentally tractable platform for advancing the science of allorecognition (Science, 2013). Using the resources and tools we and others developed we continue our studies on BHF and the evolution of blood borne immune system.

Current Role at Stanford


Advising and Mentoring
Benyamin, Rosental
benyamin@stanford.edu
(1) 831-224-2187 Postdoctoral Fellow, Weissman Lab.

Mark Alec Kowarsky
markak@stanford.edu
Doctoral program physics, Quake Lab.

Pre Major Advisees
Ratteray, Alida Nicole
aratt@stanford.edu
1 (603) 921-7328Undergrad, ENGR-BS, Junior
Philp, Charlotte Victoria
cphilp@stanford.edu
1 (650) 391-3140Undergrad, BIOE-BS, Junior
Stevens, Lydia Rose
lydiars@stanford.edu
(805) 440-9115Undergrad, UNDCL-B, Sophomore
Lim, Joseph Patrick
jlim19@stanford.edu
(501) 305-1504Undergrad, UNDCL-B, Sophomore
Kumarasinghe, Raveen Lashlen
rkumaras@stanford.edu
(510) 766-5999Undergrad, UNDCL-B, Sophomore

Education & Certifications


  • Postdoctoral Fellow, Stanford University, Stanford, California, Stem Cell Biology (2006)
  • Ph.D, Technion, Israel institute of technology, Haifa, Cell Biology (2001)
  • M.Sc, Tel-Aviv University, Tel-Aviv, Israel, Zoology (1995)
  • B.Sc, The Hebrew University of Jerusalem, Israel, Animal science (1991)

Patents


  • Ayelet Voskoboynik; Dmitry Pushkarev, Stephen Quake. "United States Patent 61/532,882; International application No. PCT/US2012/054461 Methods for obtaining a sequence. US 61/532,882, filed September 9, 2011(Pending); International application No. PCT/US2012/054461, filled September 10, 2012 (Pending); United Kingdom patent application 1216076.8 filed September 10, 2012 (Pending)"

Professional

Professional Interests


The B. schlosseri genome project
Urochordates like B. schlosseri are considered to be the closest living invertebrate relatives of vertebrates. Using a novel method for high-throughput sequencing of eukaryotic genomes, we sequenced and assembled 580 Mbp of the B. schlosseri genome. The genome assembly is comprised of nearly 14,000 intron-containing predicted genes, and 13,500 intron-less predicted genes, 40% of which could be confidently parceled into 13 (of 16 haploid) chromosomes. A comparison of homologous genes between B. schlosseri and other diverse taxonomic groups revealed genomic events underlying the evolution of vertebrates and lymphoid-mediated immunity. The B. schlosseri genome is a community resource for studying alternative modes of reproduction, natural transplantation reactions, and stem cell-mediated regeneration (Voskoboynik et al., 2013).

Isolation of a single gene, BHF, that control histocompatibility reactions in B. schlosseri.
Using the newly sequenced B. schlosseri genome, we carefully looked into a single polymorphic gene locus that governs fusion/rejection outcomes in B. schlosseri. This locus, called Fu/HC for fusion/histocompatibility, encodes multiple co-dominant alleles in natural populations. In addition, progeny from crosses between histocompatible B. schlosseri colonies are known to segregate in a manner consistent with a monogenetic trait. Using genetically Fu/HC defined lines, whole-transcriptome sequencing of 23 colonies, and a novel genomics approach, we identified BHF, the gene that encodes self/non-self and determines ?graft? outcomes in this organism. We showed that BHF is significantly upregulated in colonies poised to undergo rejection, and is highly expressed in the vasculature. Moreover, BHF knockdown arrested fusion in histocompatible pairs, while control colonies readily fused, demonstrating a functional link between BHF and fusion initiation. Our genome-wide study reveals the first fusion-rejection system understood to the point where one can reliably predict, based on a single gene, the outcome of histocompatibility reactions. These findings establish an experimentally tractable platform for advancing the science of allorecognition (Voskoboynik and Newman et al., 2013).

Publications

All Publications


  • Identification of a colonial chordate histocompatibility gene. Science Voskoboynik, A., Newman, A. M., Corey, D. M., Sahoo, D., Pushkarev, D., Neff, N. F., Passarelli, B., Koh, W., Ishizuka, K. J., Palmeri, K. J., Dimov, I. K., Keasar, C., Fan, H. C., Mantalas, G. L., Sinha, R., Penland, L., Quake, S. R., Weissman, I. L. 2013; 341 (6144): 384-387

    Abstract

    Histocompatibility is the basis by which multicellular organisms of the same species distinguish self from nonself. Relatively little is known about the mechanisms underlying histocompatibility reactions in lower organisms. Botryllus schlosseri is a colonial urochordate, a sister group of vertebrates, that exhibits a genetically determined natural transplantation reaction, whereby self-recognition between colonies leads to formation of parabionts with a common vasculature, whereas rejection occurs between incompatible colonies. Using genetically defined lines, whole-transcriptome sequencing, and genomics, we identified a single gene that encodes self-nonself and determines "graft" outcomes in this organism. This gene is significantly up-regulated in colonies poised to undergo fusion and/or rejection, is highly expressed in the vasculature, and is functionally linked to histocompatibility outcomes. These findings establish a platform for advancing the science of allorecognition.

    View details for DOI 10.1126/science.1238036

    View details for PubMedID 23888037

  • The genome sequence of the colonial chordate, Botryllus schlosseri. eLife Voskoboynik, A., Neff, N. F., Sahoo, D., Newman, A. M., Pushkarev, D., Koh, W., Passarelli, B., Fan, H. C., Mantalas, G. L., Palmeri, K. J., Ishizuka, K. J., Gissi, C., Griggio, F., Ben-Shlomo, R., Corey, D. M., Penland, L., White, R. A., Weissman, I. L., Quake, S. R. 2013; 2

    Abstract

    Botryllus schlosseri is a colonial urochordate that follows the chordate plan of development following sexual reproduction, but invokes a stem cell-mediated budding program during subsequent rounds of asexual reproduction. As urochordates are considered to be the closest living invertebrate relatives of vertebrates, they are ideal subjects for whole genome sequence analyses. Using a novel method for high-throughput sequencing of eukaryotic genomes, we sequenced and assembled 580 Mbp of the B. schlosseri genome. The genome assembly is comprised of nearly 14,000 intron-containing predicted genes, and 13,500 intron-less predicted genes, 40% of which could be confidently parceled into 13 (of 16 haploid) chromosomes. A comparison of homologous genes between B. schlosseri and other diverse taxonomic groups revealed genomic events underlying the evolution of vertebrates and lymphoid-mediated immunity. The B. schlosseri genome is a community resource for studying alternative modes of reproduction, natural transplantation reactions, and stem cell-mediated regeneration. DOI:http://dx.doi.org/10.7554/eLife.00569.001.

    View details for DOI 10.7554/eLife.00569

    View details for PubMedID 23840927

  • Identification of the Endostyle as a Stem Cell Niche in a Colonial Chordate CELL STEM CELL Voskoboynik, A., Soen, Y., Rinkevich, Y., Rosner, A., Ueno, H., Reshef, R., Ishizuka, K. J., Palmeri, K. J., Moiseeva, E., Rinkevich, B., Weissman, I. L. 2008; 3 (4): 456-464

    Abstract

    Stem cell populations exist in "niches" that hold them and regulate their fate decisions. Identification and characterization of these niches is essential for understanding stem cell maintenance and tissue regeneration. Here we report on the identification of a novel stem cell niche in Botryllus schlosseri, a colonial urochordate with high stem cell-mediated developmental activities. Using in vivo cell labeling, engraftment, confocal microscopy, and time-lapse imaging, we have identified cells with stemness capabilities in the anterior ventral region of the Botryllus' endostyle. These cells proliferate and migrate to regenerating organs in developing buds and buds of chimeric partners but do not contribute to the germ line. When cells are transplanted from the endostyle region, they contribute to tissue development and induce long-term chimerism in allogeneic tissues. In contrast, cells from other Botryllus' regions do not show comparable stemness capabilities. Cumulatively, these results define the Botryllus' endostyle region as an adult somatic stem cell niche.

    View details for DOI 10.1016/j.stem.2008.07.023

    View details for Web of Science ID 000260149800015

    View details for PubMedID 18940736

  • Striving for normality: whole body regeneration through a series of abnormal generations FASEB JOURNAL Voskoboynik, A., Simon-Blecher, N., Soen, Y., Rinkevich, B., De Tomaso, A. W., Ishizuka, K. J., Weissman, I. L. 2007; 21 (7): 1335-1344

    Abstract

    Embryogenesis and asexual reproduction are commonly considered to be coordinated developmental processes, which depend on accurate progression through a defined sequence of developmental stages. Here we report a peculiar developmental scenario in a simple chordate, Botryllus schlosseri, wherein a normal colony of individuals (zooids and buds) is regenerated from the vasculature (vascular budding) through a sequence of morphologically abnormal developmental stages. Vascular budding was induced by surgically removing buds and zooids from B. schlosseri colonies, leaving only the vasculature and the tunic that connects them. In vivo imaging and histological sections showed that the timing and morphology of developing structures during vascular budding deviated significantly from other asexual reproduction modes (the regular asexual reproduction mode in this organism and vascular budding in other botryllid species). Subsequent asexual reproduction cycles exhibited gradual regaining of normal developmental patterns, eventually leading to regeneration of a normal colony. The conversion into a normal body form suggests the activation of an alternative pathway of asexual reproduction, which involves gradual regaining of normal positional information. It presents a powerful model for studying the specification of the same body plan by different developmental programs.

    View details for DOI 10.1096/fj.06-7337com

    View details for Web of Science ID 000246117000009

    View details for PubMedID 17289924

  • Developmental cell death programs license cytotoxic cells to eliminate histocompatible partners PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Corey, D. M., rosental, B., Kowarsky, M., Sinha, R., Ishizuka, K. J., Palmeri, K. J., Quake, S. R., Voskoboynik, A., Weissman, I. L. 2016; 113 (23): 6520-6525

    Abstract

    In a primitive chordate model of natural chimerism, one chimeric partner is often eliminated in a process of allogeneic resorption. Here, we identify the cellular framework underlying loss of tolerance to one partner within a natural Botryllus schlosseri chimera. We show that the principal cell type mediating chimeric partner elimination is a cytotoxic morula cell (MC). Proinflammatory, developmental cell death programs render MCs cytotoxic and, in collaboration with activated phagocytes, eliminate chimeric partners during the "takeover" phase of blastogenic development. Among these genes, the proinflammatory cytokine IL-17 enhances cytotoxicity in allorecognition assays. Cellular transfer of FACS-purified MCs from allogeneic donors into recipients shows that the resorption response can be adoptively acquired. Transfer of 1 10(5) allogeneic MCs eliminated 33 of 78 (42%) recipient primary buds and 20 of 76 (20.5%) adult parental adult organisms (zooids) by 14 d whereas transfer of allogeneic cell populations lacking MCs had only minimal effects on recipient colonies. Furthermore, reactivity of transferred cells coincided with the onset of developmental-regulated cell death programs and disproportionately affected developing tissues within a chimera. Among chimeric partner "losers," severe developmental defects were observed in asexually propagating tissues, reflecting a pathologic switch in gene expression in developmental programs. These studies provide evidence that elimination of one partner in a chimera is an immune cell-based rejection that operates within histocompatible pairs and that maximal allogeneic responses involve the coordination of both phagocytic programs and the "arming" of cytotoxic cells.

    View details for DOI 10.1073/pnas.1606276113

    View details for Web of Science ID 000377155400052

    View details for PubMedID 27217570

  • Characterization of Ambra1 in asexual cycle of a non-vertebrate chordate, the colonial tunicate Botryllus schlosseri, and phylogenetic analysis of the protein group in Bilateria. Molecular phylogenetics and evolution Gasparini, F., Skobo, T., Benato, F., Gioacchini, G., Voskoboynik, A., Carnevali, O., Manni, L., Dalla Valle, L. 2016; 95: 46-57

    Abstract

    Ambra1 is a positive regulator of autophagy, a lysosome-mediated degradative process involved both in physiological and pathological conditions. Nowadays, Ambra1 has been characterized only in mammals and zebrafish. Through bioinformatics searches and targeted cloning, we report the identification of the complete Ambra1 transcript in a non-vertebrate chordate, the tunicate Botryllus schlosseri. Tunicata is the sister group of Vertebrata and the only chordate group possessing species that reproduce also by blastogenesis (asexual reproduction). B. schlosseri Ambra1 deduced amino acid sequence is shorter than vertebrate homologues but still contains the typical WD40 domain. qPCR analyses revealed that the level of B. schlosseri Ambra1 transcription is temporally regulated along the colonial blastogenetic cycle. By means of similarity searches we identified Wdr5 and Katnb1 as proteins evolutionarily associated to Ambra1. Phylogenetic analyses on Bilateria indicate that: (i) Wdr5 is the most related to Ambra1, so that they may derive from an ancestral gene, (ii) Ambra1 forms a group of ancient genes evolved before the radiation of the taxon, (iii) these orthologous Ambra1 share the two conserved WD40/YVTN repeat-like-containing domains, and (iv) they are characterized by ancient duplications of WD40 repeats within the N-terminal domain.

    View details for DOI 10.1016/j.ympev.2015.11.001

    View details for PubMedID 26611831

  • Botryllus schlosseri, an emerging model for the study of aging, stem cells, and mechanisms of regeneration INVERTEBRATE REPRODUCTION & DEVELOPMENT Voskoboynik, A., Weissman, I. L. 2015; 59: 33-38
  • Guidelines for the Nomenclature of Genetic Elements in Tunicate Genomes GENESIS Stolfi, A., Sasakura, Y., Chalopin, D., Satou, Y., Christiaen, L., Dantec, C., Endo, T., Naville, M., Nishida, H., Swalla, B. J., Volff, J., Voskoboynik, A., Dauga, D., Lemaire, P. 2015; 53 (1): 1-14

    Abstract

    Tunicates are invertebrate members of the chordate phylum, and are considered to be the sister group of vertebrates. Tunicates are composed of ascidians, thaliaceans, and appendicularians. With the advent of inexpensive high-throughput sequencing, the number of sequenced tunicate genomes is expected to rise sharply within the coming years. To facilitate comparative genomics within the tunicates, and between tunicates and vertebrates, standardized rules for the nomenclature of tunicate genetic elements need to be established. Here we propose a set of nomenclature rules, consensual within the community, for predicted genes, pseudogenes, transcripts, operons, transcriptional cis-regulatory regions, transposable elements, and transgenic constructs. In addition, the document proposes guidelines for naming transgenic and mutant lines.

    View details for DOI 10.1002/dvg.22822

    View details for Web of Science ID 000348656800001

    View details for PubMedID 25220678

  • Ontology for the Asexual Development and Anatomy of the Colonial Chordate Botryllus schlosseri PLOS ONE Manni, L., Gasparini, F., Hotta, K., Ishizuka, K. J., Ricci, L., Tiozzo, S., Voskoboynik, A., Dauga, D. 2014; 9 (5)

    Abstract

    Ontologies provide an important resource to integrate information. For developmental biology and comparative anatomy studies, ontologies of a species are used to formalize and annotate data that are related to anatomical structures, their lineage and timing of development. Here, we have constructed the first ontology for anatomy and asexual development (blastogenesis) of a bilaterian, the colonial tunicate Botryllus schlosseri. Tunicates, like Botryllus schlosseri, are non-vertebrates and the only chordate taxon species that reproduce both sexually and asexually. Their tadpole larval stage possesses structures characteristic of all chordates, i.e. a notochord, a dorsal neural tube, and gill slits. Larvae settle and metamorphose into individuals that are either solitary or colonial. The latter reproduce both sexually and asexually and these two reproductive modes lead to essentially the same adult body plan. The Botryllus schlosseri Ontology of Development and Anatomy (BODA) will facilitate the comparison between both types of development. BODA uses the rules defined by the Open Biomedical Ontologies Foundry. It is based on studies that investigate the anatomy, blastogenesis and regeneration of this organism. BODA features allow the users to easily search and identify anatomical structures in the colony, to define the developmental stage, and to follow the morphogenetic events of a tissue and/or organ of interest throughout asexual development. We invite the scientific community to use this resource as a reference for the anatomy and developmental ontology of B. schlosseri and encourage recommendations for updates and improvements.

    View details for DOI 10.1371/journal.pone.0096434

    View details for Web of Science ID 000335510600101

    View details for PubMedID 24789338

  • Ascidian Mitogenomics: Comparison of Evolutionary Rates in Closely Related Taxa Provides Evidence of Ongoing Speciation Events GENOME BIOLOGY AND EVOLUTION Griggio, F., Voskoboynik, A., Iannelli, F., Justy, F., Tilak, M., Xavier, T., Pesole, G., Douzery, E. J., Mastrototaro, F., Gissi, C. 2014; 6 (3): 591-605

    Abstract

    Ascidians are a fascinating group of filter-feeding marine chordates characterized by rapid evolution of both sequences and structure of their nuclear and mitochondrial genomes. Moreover, they include several model organisms used to investigate complex biological processes in chordates. To study the evolutionary dynamics of ascidians at short phylogenetic distances, we sequenced 13 new mitogenomes and analyzed them, together with 15 other available mitogenomes, using a novel approach involving detailed whole-mitogenome comparisons of conspecific and congeneric pairs. The evolutionary rate was quite homogeneous at both intraspecific and congeneric level, and the lowest congeneric rates were found in cryptic (morphologically undistinguishable) and in morphologically very similar species pairs. Moreover, congeneric nonsynonymous rates (dN) were up to two orders of magnitude higher than in intraspecies pairs. Overall, a clear-cut gap sets apart conspecific from congeneric pairs. These evolutionary peculiarities allowed easily identifying an extraordinary intraspecific variability in the model ascidian Botryllus schlosseri, where most pairs show a dN value between that observed at intraspecies and congeneric level, yet consistently lower than that of the Ciona intestinalis cryptic species pair. These data suggest ongoing speciation events producing genetically distinct B. schlosseri entities. Remarkably, these ongoing speciation events were undetectable by the cox1 barcode fragment, demonstrating that, at low phylogenetic distances, the whole mitogenome has a higher resolving power than cox1. Our study shows that whole-mitogenome comparative analyses, performed on a suitable sample of congeneric and intraspecies pairs, may allow detecting not only cryptic species but also ongoing speciation events.

    View details for DOI 10.1093/gbe/evu041

    View details for Web of Science ID 000334578100014

    View details for PubMedID 24572017

  • Repeated, Long-Term Cycling of Putative Stem Cells between Niches in a Basal Chordate DEVELOPMENTAL CELL Rinkevich, Y., Voskoboynik, A., Rosner, A., Rabinowitz, C., Paz, G., Oren, M., Douek, J., Alfassi, G., Moiseeva, E., Ishizuka, K. J., Palmeri, K. J., Weissman, I. L., Rinkevich, B. 2013; 24 (1): 76-88

    Abstract

    The mechanisms that sustain stem cells are fundamental to tissue maintenance. Here, we identify "cell islands" (CIs) as a niche for putative germ and somatic stem cells in Botryllus schlosseri, a colonial chordate that undergoes weekly cycles of death and regeneration. Cells within CIs express markers associated with germ and somatic stem cells and gene products that implicate CIs as signaling centers for stem cells. Transplantation of CIs induced long-term germline and somatic chimerism, demonstrating self-renewal and pluripotency of CI cells. Cell labeling and in vivo time-lapse imaging of CI cells reveal waves of migrations from degrading CIs into developing buds, contributing to soma and germline development. Knockdown of cadherin, which is highly expressed within CIs, elicited the migration of CI cells to circulation. Piwi knockdown resulted in regeneration arrest. We suggest that repeated trafficking of stem cells allows them to escape constraints imposed by the niche, enabling self-preservation throughout life.

    View details for DOI 10.1016/j.devcel.2012.11.010

    View details for Web of Science ID 000316305200007

  • Chimerism a natural ability to tolerate kin, evolutionary traits connecting mammalian and protochordates ISJ-INVERTEBRATE SURVIVAL JOURNAL Voskoboynik, A. 2009; 6 (1): S9-S20
  • Stem Cells, Chimerism and Tolerance: Lessons from Mammals and Ascidians Stem Cells in Marine Organisms Voskoboynik, A., Rinkevich, B., Weissman, I. L. Springer Netherlands. 2009: 281-308
  • A conserved role of the VEGF pathway in angiogenesis of an ectodermally-derived vasculature DEVELOPMENTAL BIOLOGY Tiozzo, S., Voskoboynik, A., Brown, F. D., De Tomaso, A. W. 2008; 315 (1): 243-255

    Abstract

    Angiogenesis, the growth and remodeling of a vascular network, is an essential process during development, growth and disease. Here we studied the role of the vascular endothelial growth factor receptor (VEGFR) in experimentally-induced angiogenesis in the colonial ascidian Botryllus schlosseri (Tunicata, Ascidiacea). The circulatory system of B. schlosseri is composed of two distinct, but interconnected regions: a plot of sinuses and lacunae which line the body, and a transparent, macroscopic extracorporeal vascular network. The vessels of the extracorporeal vasculature are morphologically inverted in comparison to the vasculature in vertebrates: they consist of a single layer of ectodermally-derived cells with the basal lamina lining the lumen of the vessel. We found that when the peripheral circulatory system of a colony is surgically removed, it can completely regenerate within 24 to 48 h and this regeneration is dependent on proper function of the VEGF pathway: siRNA-mediated knockdown of the VEGFR blocked vascular regeneration, and interfered with vascular homeostasis. In addition, a small molecule, the VEGFR kinase inhibitor PTK787/ZK222584, phenocopied the siRNA knockdown in a reversible manner. Despite the disparate germ layer origins and morphology of the vasculature, the developmental program of branching morphogenesis during angiogenesis is controlled by similar molecular mechanisms, suggesting that the function of the VEGF pathway may be co-opted during the regeneration of an ectoderm-derived tubular structure.

    View details for DOI 10.1016/j.ydbio.2007.12.035

    View details for Web of Science ID 000253750300019

    View details for PubMedID 18234178

  • BS-Cadherin in the colonial urochordate Botryllus schlosseri: One protein, many functions DEVELOPMENTAL BIOLOGY Rosner, A., Rabinowitz, C., Moiseeva, E., Voskoboynik, A., Rinkevich, B. 2007; 304 (2): 687-700

    Abstract

    Botryllus schlosseri is a colonial urochordate composed of coexisting modules of three asexually derived generations, the zooids and two cohorts of buds, each at disparate developmental stage. Functional zooids are replaced weekly by the older generation of buds through a highly synchronized developmental cycle called blastogenesis (which is, in turn, divided into four major stages, A to D). In this study, we examined the mode of expression of BS-cadherin, a 130-kDa transmembrane protein isolated from this species, during blastogenesis. BS-Cadherin is expressed extensively in internal organs of developing buds, embryos, ampullae and, briefly, in the digestive system of zooids at early blastogenic stage D (in contrast to low mRNA expression at this stage). In vitro trypsin assays on single-cell suspensions prepared from blastogenic stage D zooids, confirmed that BS-cadherin protein is expressed on cell surfaces and is, therefore, functional. BS-Cadherin expression is also upregulated in response to various stress conditions, such as oxidative stress, injury and allorecognition. It plays an important role in colony morphogenesis, because siRNA knockdown during D/A blastogenic transition causes chaotic colonial structures and disrupts oocytes homing onto their bud niches. These results reveal that BS-cadherin protein functions are exerted through a specific spatiotemporal pattern and fluctuating expression levels, in both development/regular homeostasis and in response to various stress conditions.

    View details for DOI 10.1016/j.ydbio.2007.01.018

    View details for Web of Science ID 000245819600019

    View details for PubMedID 17316601

  • fester, a Candidate allorecognition receptor from a primitive chordate IMMUNITY Nyholm, S. V., Passegue, E., Ludington, W. B., Voskoboynik, A., Mitchel, K., Weissman, I. L., De Tomaso, A. W. 2006; 25 (1): 163-173

    Abstract

    Histocompatibility in the primitive chordate, Botryllus schlosseri, is controlled by a single, highly polymorphic locus, the FuHC. By taking a forward genetic approach, we have identified a locus encoded near the FuHC, called fester, which is polymorphic, polygenic, and inherited in distinct haplotypes. Somatic diversification occurs through extensive alternative splicing, with each individual expressing a unique repertoire of splice forms, both membrane bound and potentially secreted, all expressed in tissues intimately associated with histocompatibility. Functional studies, via both siRNA-mediated knockdown and direct blocking by monoclonal antibodies raised against fester, were able to disrupt predicted histocompatibility outcomes. The genetic and somatic diversity, coupled to the expression and functional data, suggests that fester is a receptor involved in histocompatibility.

    View details for DOI 10.1016/j.immuni.2006.04.011

    View details for Web of Science ID 000239713000019

    View details for PubMedID 16860765

  • Macrophage involvement for successful degeneration of apoptotic organs in the colonial urochordate Botryllus schlosseri JOURNAL OF EXPERIMENTAL BIOLOGY Voskoboynik, A., Rinkevich, B., WEISS, A., Moiseeva, E., Reznick, A. Z. 2004; 207 (14): 2409-2416

    Abstract

    Apoptosis is an important tool for shaping developing organs and for maintaining cellular homeostasis. In the colonial urochordate Botryllus schlosseri, apoptosis is also the hallmark end point in blastogenesis, a cyclical and weekly developmental phenomenon. Then the entire old generation of zooids are eliminated (resorbed) by a process that lasts 24-36 h. Administration of the antioxidant butylated hydroxytoluene (BHT) resulted in resorption being arrested by 1-8 days on average. At high doses (2.5-15.0 mg BHT l(-1)) resorption was completed only after removal of BHT. Colonies that were not removed in time, died. In treated colonies, although DNA fragmentation was high, tissues and organs that would normally have died, survived, and the general oxidative levels of lipids were reduced. Blood vessels were widened, containing aggregates of blood cells with a significantly increased proportion of empty macrophage-like cells without inclusion. In colonies rescued from BHT treatment, resorption of zooids started immediately and was completed within a few days. We propose three possible mechanisms as to how BHT may affect macrophage activity: (1) by interrupting signals that further promote apoptosis; (2) through the respiratory burst initiated following a phagocytic stimulus; and (3) by reducing lipid oxidation and changing cell surface markers of target cells. Our results point, for the first time, to the role of phagocytic cells in the coordination of death and clearance signals in blastogenesis.

    View details for DOI 10.1242/jeb.01045

    View details for Web of Science ID 000222883000010

    View details for PubMedID 15184513

  • Rejuvenescence and extension of an urochordate life span following a single, acute administration of an anti-oxidant, butylated hydroxytoluene MECHANISMS OF AGEING AND DEVELOPMENT Voskoboynik, A., Reznick, A. Z., Rinkevich, B. 2002; 123 (9): 1203-1210

    Abstract

    Two commonly accepted metabolic theories of aging interpret senescence either in terms of the rate of living, where a fixed total metabolic potential is consumed over an expected lifetime (after which the organism wears out and dies) or, in terms of accumulative oxidative damage resulting in progressive and irreversible changes in metabolic pathways. Protocols based on restricted diets, chronically administered anti-oxidants and the use of established lines of organisms resistant to free radical damage support the metabolic theories of aging by revealing, in many cases, significant extensions of life spans or dramatic anti-aging effects. To test the universality of these metabolic hypotheses of aging, we acutely treated ramets (clonal replicates) from old, long-lived colonies of the urochordate Botryllus schlosseri with lethal doses of the anti-oxidant butylated hydroxytoluene (BHT). This group of organisms has a weekly cyclical and highly synchronized developmental process (blastogenesis), during which all existing zooids are removed by massive apoptosis and phagocytosis processes. In animals treated with BHT, blastogenesis was completely arrested and colonies deteriorated to a morphologically chaotic state. Rescued ramets resorbed BHT treated zooids, regenerated entirely new sets of zooids and then revealed: (1) rejuvenescence and enhanced growth rates and in many cases, (2) up to 4.6 times extension of post-treatment life expectancy. Both metabolic theories for senescence were therefore falsified in B. schlosseri. The possible existence of an aging clock that can be set by the environment is suggested.

    View details for Web of Science ID 000177238800001

    View details for PubMedID 12020943

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