Impaired neurogenesis, learning and memory and low seizure threshold associated with loss of neural precursor cell survivin
1 KU Leuven, VIB Vesalius Research Center (VRC), Herestraat 49, Gasthuisberg O&N1, B3000 Leuven, Belgium
2 KU Leuven Laboratory of Biological Psychology, Tiensestraat 102, B3000 Leuven, Belgium
3 Dept of Pharmacology, University of Milan, via Vanvitelli 32, Milan, Italy
4 Istituto di Neuroscienze, Consiglio Nazionale delle Ricerche, via G. Moruzzi 1, 56100 Pisa, Italy
5 KU Leuven, Laboratory for Neurobiology and Gene Therapy, Kapucijnenvoer 33, B3000 Leuven, Belgium
6 Developmental Biology Institute of Marseille, NMDA CNRS, INSERM, Univ. de Mediterranee, Campus de Luminy, 13288 Marseille, France
7 Department of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, Texas, 75390-9070 USA
8 Department of Cellular and Molecular Medicine & Neuroscience Program, University of Ottawa, 451 Smyth Road, Ottawa, K1H 8M5 Canada
9 Laboratory of Molecular Neuropathology, Centre for Integrative Biology, University of Trento, via delle Regole 101, 38060 Trento, Italy
10 Center for Blood Research, Faculty of Medicine, University of British Columbia, 2350 Health Sciences Mall, Vancouver, V6T 1Z3 Canada
BMC Neuroscience 2010, 11:2 doi:10.1186/1471-2202-11-2Published: 5 January 2010
Survivin 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.
To 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.
The findings highlight the critical role that survivin plays during neural development, deficiencies of which dramatically impact on postnatal neural function.