Neuronal functions of FOXO/DAF-16

Abstract

The FOXO family of transcription factors plays a conserved role in longevity and tissue homeostasis across species. In the mammalian nervous system, emerging evidence has implicated FOXOs in cognitive performance, stem cell maintenance, regeneration, and protection against stress. Much of what we know about neuronal functions of FOXO emerged from recent studies in C. elegans. Similar to mammalian FOXO, the worm FOXO ortholog, called DAF-16, regulates learning and memory, regeneration, and stress resistance in neurons. Here, we discuss the current state of our knowledge of FOXO's functions in neurons in mammals and invertebrates, and highlight areas where our understanding is limited. Defining the function of FOXO factors in the healthy, aged, and diseased brain may have important implications for improving healthspan and treating neurodegenerative disease.

Keywords: DAF-16; FOXO; aging; brain; insulin/IGF signaling.

Fig.1

The insulin/IGF signaling pathway. FOXO transcription factors are inhibited by insulin/IGF signaling. In the absence of insulin/IGF binding, FOXOs regulate a number of cellular processes (blue), which in turn affect tissue homeostasis and organismal longevity. Inset shows the orthologous pathway in C. elegans.

Fig.2

FOXOs have been implicated in learning and memory in C. elegans and mice. (A) Summary of the evidence implicating DAF-16 in the regulation of learning and memory in C. elegans. (B) Schematic representation of the domains of the hippocampus that express different FOXO isoforms in the mouse. The upper panel depicts a side view of the rodent brain. A coronal section at the level of the hippocampus (dotted line in the side view) is shown in the center. The bottom image shows a zoomed-in schematic of the hippocampus, and indicates where the different mammalian FOXO isoforms are expressed.

Fig.3

The neuronal functions of FOXO transcription factors in C. elegans and mammals.