Concomitant inactivation of foxo3a and fancc or fancd2 reveals a two-tier protection from oxidative stress-induced hydrocephalus.
OBJECTIVE
This study seeks at investigating the cause of hydrocephalus, and at identifying therapeutic targets for the prevention of hydrocephalus.


RESULTS
In this study, we show that inactivation of the Foxo3a gene in two mouse models of Fanconi anemia (FA) leads to the development of hydrocephalus in late embryonic stage and after birth. More than 50% of Foxo3a(-/-) Fancc(-/-) or Foxo3a(-/-) Fancd2(-/-) mice die during embryonic development or within 6 months of life as a result of hydrocephalus characterized by cranial distortion, dilation of the ventricular system, reduced thickness of the cerebral cortex, and disorganization of the ependymal cilia and subcommissural organ. Combined deficiency of Foxo3a and Fancc or Fancd2 not only impairs the self-renewal capacity but also markedly increases the apoptosis of neural stem and progenitor cells (NSPCs), leading to defective neurogenesis. Increased accumulation of reactive oxygen species (ROS) and subsequently de-regulated mitosis and ultimately apoptosis in the neural stem or progenitor cells is identified as one of the potential mechanisms of congenital obstructive hydrocephalus.


METHODS
The work unravels a two-tier protective mechanism for preventing oxidative stress-induced hydrocephalus.


CONCLUSIONS
The deletion of Foxo3a in FA mice increased the accumulation of ROS and subsequently de-regulated mitosis and ultimately apoptosis in the NSPCs, leading to hydrocephalus development.
1 Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center , Cincinnati, Ohio.
Xiaoli
X
Li
Liang
L
Li
Jie
J
Li
Jared
J
Sipple
Jonathan
J
Schick
Parinda A
PA
Mehta
Stella M
SM
Davies
Biplab
B
Dasgupta
Ronald R
RR
Waclaw
Qishen
Q
Pang
D000818:Animals; D005199:Fanconi Anemia / Q000235:genetics / Q000378:metabolism; D052218:Fanconi Anemia Complementation Group C Protein / Q000172:deficiency / Q000378:metabolism*; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000172:deficiency / Q000378:metabolism*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006849:Hydrocephalus / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism
C497652:Fancc protein, mouse; C499904:Fancd2 protein, mouse; D052218:Fanconi Anemia Complementation Group C Protein; D052236:Fanconi Anemia Complementation Group D2 Protein; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D017382:Reactive Oxygen Species