FOXO in Neural Cells and Diseases of the Nervous System

Abstract

The evolutionarily conserved FOXO family of transcription factors has emerged as a significant arbiter of neural cell fate and function in mammals. From the neural stem cell (NSC) state through mature neurons under both physiological and pathological conditions, they have been found to modulate neural cell survival, stress responses, lineage commitment, and neuronal signaling. Lineage-specific FOXO knockout mice have provided an invaluable tool for the dissection of FOXO biology in the nervous system. Within the NSC compartments of the brain, FOXOs are required for the maintenance of NSC quiescence and for the clearance of reactive oxygen species. Within mature neurons, FOXO transcriptional activity is essential for the prevention of age-dependent axonal degeneration. Acutely, FOXO3 has been found to cause axonal degeneration upon withdrawal of neurotrophic factors. In more active neural signaling, FOXO6 promotes increased dendritic spine density of hippocampal neurons and is required for the consolidation of memories. In addition to the central nervous system (CNS), FOXOs also influence the functionality of the peripheral nervous system (PNS). FOXO1 knockout within the PNS results in a reduction of sympathetic tone and decreased levels of brain-derived norepinephrine and lower energy expenditure. FOXO3 knockout mice have impaired hearing which may be due to defects in synapse localization within the ear. Given the scope of FOXO activities in both the CNS and PNS, it will be of interest to study FOXOs within the context of neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis. From within the nervous system, FOXOs may also regulate important parameters such as whole-body metabolism, motor function, and catecholamine production, making FOXOs key players in physiologic homeostasis.

Keywords: Aging; FOXO; Knockout; Nervous system; Neural stem cell; Neurodegeneration; Neurodevelopment; Neurosignaling.

Figure 1

Domain map and post-translaional modifications that influence FOXO1 & FOXO3 apoptotic activity within neurons. (A) Annotated FOXO1 protein numbered vs. the human sequence. Within the domain structure the forkhead domain is colored blue, nuclear localization signals are red, nuclear export signals are green and the transactivation domain is yellow. Modifications that promote cell death are marked with red lines, green lines mark modifications that promote survival and blue lines mark modifications with conflicting reports on survival. (B) Annotated FOXO3 protein numbered vs. the human sequence. Same color scheme as A.

Figure 1

Domain map and post-translaional modifications that influence FOXO1 & FOXO3 apoptotic activity within neurons. (A) Annotated FOXO1 protein numbered vs. the human sequence. Within the domain structure the forkhead domain is colored blue, nuclear localization signals are red, nuclear export signals are green and the transactivation domain is yellow. Modifications that promote cell death are marked with red lines, green lines mark modifications that promote survival and blue lines mark modifications with conflicting reports on survival. (B) Annotated FOXO3 protein numbered vs. the human sequence. Same color scheme as A.