Impaired neurogenesis, learning and memory and low seizure threshold associated with loss of neural precursor cell survivin

Vanessa Coremans,Amelia Eisch,Michaël Moons,Jonathan Cremer,Yuri Bozzi,Diane Lagace,Edward M Conway,Veerle Reumers,Veerle Baekelandt,Matteo Caleo,Astrid Devriese,Harold Cremer,Tom Janssens,Tariq Ahmed,Flavia Antonucci,Detlef Balschun,Rudi D'Hooge

doi:10.1186/1471-2202-11-2

Abstract

BackgroundSurvivin is a unique member of the inhibitor of apoptosis protein (IAP) family in that it exhibits antiapoptotic properties and also promotes the cell cycle and mediates mitosis as a chromosome passenger protein. Survivin is highly expressed in neural precursor cells in the brain, yet its function there has not been elucidated.ResultsTo examine the role of neural precursor cell survivin, we first showed that survivin is normally expressed in periventricular neurogenic regions in the embryo, becoming restricted postnatally to proliferating and migrating NPCs in the key neurogenic sites, the subventricular zone (SVZ) and the subgranular zone (SGZ). We then used a conditional gene inactivation strategy to delete the survivin gene prenatally in those neurogenic regions. Lack of embryonic NPC survivin results in viable, fertile mice (SurvivinCamcre) with reduced numbers of SVZ NPCs, absent rostral migratory stream, and olfactory bulb hypoplasia. The phenotype can be partially rescued, as intracerebroventricular gene delivery of survivin during embryonic development increases olfactory bulb neurogenesis, detected postnatally. SurvivinCamcre brains have fewer cortical inhibitory interneurons, contributing to enhanced sensitivity to seizures, and profound deficits in memory and learning.ConclusionsThe findings highlight the critical role that survivin plays during neural development, deficiencies of which dramatically impact on postnatal neural function.

Highlights

Survivin is a unique member of the inhibitor of apoptosis protein (IAP) family in that it exhibits antiapoptotic properties and promotes the cell cycle and mediates mitosis as a chromosome passenger protein
Survivin is expressed in precursor cells in the neurogenic areas of the brain In situ hybridization using a probe against full length survivin allowed assessment of the spatiotemporal expression of survivin during embryonic development
At E12.5, expression of survivin overlapped with Dlx1, a marker for mitotic cells in the MGE and lateral ganglionic eminence (LGE) [24] (Figure 1A, D) and neurogenin 2 (Ngn2) [25], a marker for dividing precursors in the neocortex (Figure 1A, C)

Summary

Introduction

Survivin is a unique member of the inhibitor of apoptosis protein (IAP) family in that it exhibits antiapoptotic properties and promotes the cell cycle and mediates mitosis as a chromosome passenger protein. In the subgranular zone (SGZ) of the hippocampus, newborn NPCs migrate, but for shorter distances, into the granule cell layer, where they become excitatory granule cells [4] From these neurogenic sites, adult-generated neurons integration of new neurons in the developing and adult brain. Survivin is a member of the inhibitor of apoptotis protein (IAP) family, that promotes the cell cycle and is a chromosome passenger protein [20,21] During embryonic development, it is expressed by several tissues, but is prominent in the nervous system [22]. Inactivation of the survivin gene in neuroepithelial cells early in development [23] results in massive apoptosis throughout the central nervous system, with total destruction of the architecture of the brain and lethality The severity of this phenotype precluded investigators from delineating the specific role of neural precursor cell survivin on postnatal neural function

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Conclusion