Role of the 2 zebrafish survivin genes in vasculo-angiogenesis, neurogenesis, cardiogenesis and hematopoiesis

BackgroundNormal growth and development of organisms requires maintenance of a dynamic balance between systems that promote cell survival and those that induce apoptosis. The molecular mechanisms that regulate these processes remain poorly understood, and thus further in vivo study is required. Survivin is a member of the inhibitor of apoptosis protein (IAP) family, that uniquely also promotes mitosis and cell proliferation. Postnatally, survivin is hardly detected in most tissues, but is upregulated in all cancers, and as such, is a potential therapeutic target. Prenatally, survivin is also highly expressed in several tissues. Fully delineating the properties of survivin in vivo in mice has been confounded by early lethal phenotypes following survivin gene inactivation.ResultsTo gain further insights into the properties of survivin, we used the zebrafish model. There are 2 zebrafish survivin genes (Birc5a and Birc5b) with overlapping expression patterns during early development, prominently in neural and vascular structures. Morpholino-induced depletion of Birc5a causes profound neuro-developmental, hematopoietic, cardiogenic, vasculogenic and angiogenic defects. Similar abnormalities, all less severe except for hematopoiesis, were evident with suppression of Birc5b. The phenotypes induced by morpholino knockdown of one survivin gene, were rescued by overexpression of the other, indicating that the Birc5 paralogs may compensate for each. The potent vascular endothelial growth factor (VEGF) also entirely rescues the phenotypes induced by depletion of either Birc5a and Birc5b, highlighting its multi-functional properties, as well as the power of the model in characterizing the activities of growth factors.ConclusionOverall, with the zebrafish model, we identify survivin as a key regulator of neurogenesis, vasculo-angiogenesis, hematopoiesis and cardiogenesis. These properties of survivin, which are consistent with those identified in mice, indicate that its functions are highly conserved across species, and point to the value of the zebrafish model in understanding the role of this IAP in the pathogenesis of human disease, and for exploring its potential as a therapeutic target.

[1]  J. Diebold,et al.  Developmentally regulated expression of the novel cancer anti-apoptosis gene survivin in human and mouse differentiation. , 1998, The American journal of pathology.

[2]  A. Schimmer.  Inhibitor of Apoptosis Proteins: Translating Basic Knowledge into Clinical Practice , 2004, Cancer Research.

[3]  S. Fraser,et al.  FGF Signaling Mediates Regeneration of the Differentiating Cerebellum through Repatterning of the Anterior Hindbrain and Reinitiation of Neuronal Migration , 2006, The Journal of Neuroscience.

[4]  Kim Dan Nguyen,et al.  Zebrafish Foxd3 is required for development of a subset of neural crest derivatives. , 2006, Developmental biology.

[5]  D. Collen,et al.  Survivin-dependent angiogenesis in ischemic brain: molecular mechanisms of hypoxia-induced up-regulation. , 2003, The American journal of pathology.

[6]  T. Zhong.  Zebrafish genetics and formation of embryonic vasculature. , 2005, Current topics in developmental biology.

[7]  B. Weinstein,et al.  In vivo imaging of embryonic vascular development using transgenic zebrafish. , 2002, Developmental biology.

[8]  Marina Mione,et al.  How to create the vascular tree? (Latest) help from the zebrafish. , 2008, Pharmacology & therapeutics.

[9]  Kris Vleminckx,et al.  A genetic Xenopus laevis tadpole model to study lymphangiogenesis , 2005, Nature Medicine.

[10]  D. Stainier,et al.  A common progenitor for haematopoietic and endothelial lineages in the zebrafish gastrula , 2006, Nature.

[11]  D. Altieri,et al.  A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma , 1997, Nature Medicine.

[12]  P. Carmeliet,et al.  VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death , 2003, Nature Genetics.

[13]  S. Pollefeyt,et al.  Deficiency of survivin in transgenic mice exacerbates Fas-induced apoptosis via mitochondrial pathways. , 2002, Gastroenterology.

[14]  T. Acker,et al.  Direct Stimulation of Adult Neural Stem Cells In Vitro and Neurogenesis In Vivo by Vascular Endothelial Growth Factor , 2004, Brain pathology.

[15]  A. Mazabraud,et al.  Survivin increased vascular development during Xenopus ontogenesis. , 2006, Differentiation; research in biological diversity.

[16]  I. Stalmans.  Role of the vascular endothelial growth factor isoforms in retinal angiogenesis and DiGeorge syndrome. , 2005, Verhandelingen - Koninklijke Academie voor Geneeskunde van Belgie.

[17]  K. Plate,et al.  Different networks, common growth factors: shared growth factors and receptors of the vascular and the nervous system , 2007, Acta Neuropathologica.

[18]  Sally Temple,et al.  Endothelial Cells Stimulate Self-Renewal and Expand Neurogenesis of Neural Stem Cells , 2004, Science.

[19]  T. Suda,et al.  A role of EphB4 receptor and its ligand, ephrin-B2, in erythropoiesis. , 2002, Biochemical and biophysical research communications.

[20]  S. Horne,et al.  Restricted expression of cardiac myosin genes reveals regulated aspects of heart tube assembly in zebrafish. , 1999, Developmental biology.

[21]  J. Eisen,et al.  Motoneuron fate specification revealed by patterned LIM homeobox gene expression in embryonic zebrafish. , 1995, Development.

[22]  G. Hauptmann,et al.  Two-color whole-mount in situ hybridization to vertebrate and Drosophila embryos. , 1994, Trends in genetics : TIG.

[23]  C. Brenner,et al.  p53 Activation by Knockdown Technologies , 2007, PLoS genetics.

[24]  R. Adams.  Vascular patterning by Eph receptor tyrosine kinases and ephrins. , 2002, Seminars in cell & developmental biology.

[25]  C. Verfaillie,et al.  The Role of Survivin in Angiogenesis during Zebrafish Embryonic Development. , 2006 .

[26]  Jeffrey M. Rosenstein,et al.  New roles for VEGF in nervous tissue—beyond blood vessels , 2004, Experimental Neurology.

[27]  C. Nüsslein-Volhard,et al.  Left-right pattern of cardiac BMP4 may drive asymmetry of the heart in zebrafish. , 1997, Development.

[28]  J. Reed,et al.  Birc2 (cIap1) regulates endothelial cell integrity and blood vessel homeostasis , 2007, Nature Genetics.

[29]  H. Yost,et al.  Cardiac neural crest contributes to cardiomyogenesis in zebrafish. , 2003, Developmental biology.

[30]  R. Altura,et al.  Lack of endothelial cell survivin causes embryonic defects in angiogenesis, cardiogenesis, and neural tube closure. , 2007, Blood.

[31]  Hui Liu,et al.  Requirements for survivin in terminal differentiation of erythroid cells and maintenance of hematopoietic stem and progenitor cells , 2007, The Journal of experimental medicine.

[32]  M. Fishman,et al.  Vessel patterning in the embryo of the zebrafish: guidance by notochord. , 1997, Developmental biology.

[33]  Fengzhi Li,et al.  Survivin study: An update of “What is the next wave?” , 2006, Journal of cellular physiology.

[34]  C. Duckett,et al.  Inhibitor of apoptosis proteins in eukaryotic evolution and development: a model of thematic conservation. , 2008, Developmental cell.

[35]  L. Leatherbury,et al.  Cardiac neural crest in zebrafish embryos contributes to myocardial cell lineage and early heart function , 2003, Developmental dynamics : an official publication of the American Association of Anatomists.

[36]  D. Vaux,et al.  Survivin and the inner centromere protein INCENP show similar cell-cycle localization and gene knockout phenotype , 2000, Current Biology.

[37]  C. Zimmer,et al.  Purification of neuronal precursors from the adult mouse brain: comprehensive gene expression analysis provides new insights into the control of cell migration, differentiation, and homeostasis , 2004, Molecular and Cellular Neuroscience.

[38]  M. Halpern,et al.  Genes dependent on zebrafish cyclops function identified by AFLP differential gene expression screen , 2000, Genesis.

[39]  D. Altieri.  New wirings in the survivin networks , 2008, Oncogene.

[40]  J. Fangusaro,et al.  Essential Role for Survivin in Early Brain Development , 2005, The Journal of Neuroscience.

[41]  B. Györffy,et al.  Single-nucleotide polymorphisms of VEGF gene are associated with risk of congenital valvuloseptal heart defects. , 2006, American heart journal.

[42]  R. Kerbel,et al.  Marked induction of the IAP family antiapoptotic proteins survivin and XIAP by VEGF in vascular endothelial cells. , 1999, Biochemical and biophysical research communications.

[43]  C. Verfaillie,et al.  The role of survivin in angiogenesis during zebrafish embryonic development , 2007, BMC Developmental Biology.

[44]  S. Fukuda,et al.  Survivin, a cancer target with an emerging role in normal adult tissues , 2006, Molecular Cancer Therapeutics.

[45]  D. Yelon,et al.  Cardiac development in zebrafish: coordination of form and function. , 2002, Seminars in cell & developmental biology.

[46]  K. Shiraki,et al.  Survivin initiates procaspase 3/p21 complex formation as a result of interaction with Cdk4 to resist Fas-mediated cell death , 2000, Oncogene.

[47]  Gabriel Acevedo-Bolton,et al.  Intracardiac fluid forces are an essential epigenetic factor for embryonic cardiogenesis , 2003, Nature.

[48]  S. Conway,et al.  Cardiovascular Development and the Colonizing Cardiac Neural Crest Lineage , 2007, TheScientificWorldJournal.

[49]  E. Weinberg,et al.  Cloning and characterization of vascular endothelial growth factor (VEGF) from zebrafish, Danio rerio. , 1998, Biochimica et biophysica acta.

[50]  A. C. Ma,et al.  The role of phospholipase C gamma 1 in primitive hematopoiesis during zebrafish development. , 2007, Experimental hematology.

[51]  C. Kimmel,et al.  Stages of embryonic development of the zebrafish , 1995, Developmental dynamics : an official publication of the American Association of Anatomists.

[52]  M. Fey,et al.  Inflammation-associated Cell Cycle–independent Block of Apoptosis by Survivin in Terminally Differentiated Neutrophils , 2004, The Journal of experimental medicine.