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


RESULTS
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.


CONCLUSIONS
The findings highlight the critical role that survivin plays during neural development, deficiencies of which dramatically impact on postnatal neural function.
Coremans
Vanessa
V
KU Leuven, VIB Vesalius Research Center, Herestraat 49, Gasthuisberg O&N1, B3000 Leuven, Belgium.
Ahmed
Tariq
T
Balschun
Detlef
D
D'Hooge
Rudi
R
DeVriese
Astrid
A
Cremer
Jonathan
J
Antonucci
Flavia
F
Moons
Michaël
M
Baekelandt
Veerle
V
Reumers
Veerle
V
Cremer
Harold
H
Eisch
Amelia
A
Lagace
Diane
D
Janssens
Tom
T
Bozzi
Yuri
Y
Caleo
Matteo
M
Conway
Edward M
EM
D000818:Animals; D001921:Brain / Q000254:growth & development / Q000473:pathology / Q000503:physiopathology*; D003072:Cognition Disorders / Q000473:pathology / Q000503:physiopathology*; D020868:Gene Silencing; D051034:Inhibitor of Apoptosis Proteins; D007395:Interneurons / Q000473:pathology / Q000502:physiology; D007859:Learning Disabilities / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008569:Memory Disorders / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009433:Neural Inhibition / Q000502:physiology; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000473:pathology / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins; D012640:Seizures / Q000473:pathology / Q000503:physiopathology*; D055153:Stem Cell Niche / Q000254:growth & development / Q000473:pathology / Q000503:physiopathology; D013234:Stem Cells / Q000473:pathology / Q000502:physiology*; D000077022:Survivin
C117749:Birc5 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D000077022:Survivin