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

Abstract

Background Normal 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. Results To 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. Conclusion Overall, 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.

Nanoformulated cell-penetrating survivin mutant and its dual actions

“…Several studies have reported the essential role of survivin in premature brain development, and that defects in its expression exhibited abnormal brain hypoplasty and immature fetal deaths. 4,57 It was also reported to have neuroprotective effects where it colocalized with active Cas-3 and protected astrocytes after brain injury. 58 Given the role of endogenous survivin in cell-cycle progression, it plays a prominent role in the spindle-fiber formation interacting with the microtubules and organizes the CPC, complexing with aurora B kinases and INCENP.…”

Netrin-1 role in angiogenesis: To be or not to be a pro-angiogenic factor?

“…6 In this direction, it is noteworthy to mention that netrin-1 disruption phenotype closely resembles that observed after silencing of three proteins involved in anti-apoptotic signaling in zebrafish, two IAP, BIRC5 and survivin, and the VEGF receptor Neuropilin-1: in each case, excess of apoptosis induced by silencing of each of these genes results in absence and/or abnormalities of ISVs that are similar to those observed in netrin-1a absence. 25,34,35 This was an argument in favor of netrin-1 pro-survival effect upon developmental angiogenesis. We have indeed observed that netrin-1 silencing leads to increase cell death in zebrafish embryos and that ISVs abnormalities could be restored by treatment of the embryos with antiapoptotic drug targeting caspases activity.…”

Control of Programmed Cell Death During Zebrafish Embryonic Development

“…Indeed, the knockdown of birc5a leads to multiple defects including in the nervous system, the cardiovascular system and the hematopoietic system. Interestingly, this phenotype was rescued by ectopic expression of both birc5 paralogs, suggesting the existence of functional redundancy during embryogenesis [20,21].…”