Concomitant inactivation of foxo3a and fancc or fancd2 reveals a two-tier protection from oxidative stress-induced hydrocephalus

Xiaoli Li, Liang Li, Jie Li, Jared Sipple, Jonathan Schick, Parinda A Mehta, Stella M Davies, Biplab Dasgupta, Ronald R Waclaw, Qishen Pang
Antioxidants & Redox Signaling 2014 October 20, 21 (12): 1675-92

AIMS: 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.

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

CONCLUSION: 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.

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