Insulin-Like Growth Factor Signaling and Actions in Brain

Abstract

The insulin-like growth factor (IGF) system is expressed in most tissues and organs during embryogenesis and throughout adult life. In particular, it is abundantly expressed during development of the nervous system, playing a key role in this process. The IGF system comprises the ligands IGF-1 and -2, their cognate receptors, and six IGF-binding proteins (IGFBPs), which modulate bioavailability and receptor targeting of the IGFs. IGFBP-modulated interaction of the IGF ligands with the IGF-1 receptor activates, via insulin receptor substrates 1 and 2, two major intracellular signaling pathways, namely, the mitogen-activated protein kinase or the phosphoinositol-3 kinase pathway. In vitro studies have demonstrated that the IGF ligands, via the above pathways, promote differentiation and proliferation and sustain survival, preventing apoptosis of neuronal and brain-derived cells. Furthermore, the IGF system appears to be involved in the regulation of many brain metabolic functions, including uptake and utilization of glucose, the major fuel of the nervous system. Studies of transgenic mice overexpressing components of the IGF system or mice with disruptions of the same genes have clearly shown that the IGF system plays a key role in vivo. IGF and similar growth factor systems do not act in isolation. Hence, the presence of other neuroendocrine factors (growth factors, cytokine, and hormones) may further modulate IGF’s biological activity and cellular responses in the nervous system. The availability of animal models for brain injury and neuronal degeneration has allowed the investigation of the role of IGF-1 in prevention and rescue of damaged neuronal cells. These studies have pointed to the potential therapeutic use of IGF-1 alone or in combination with other neuroendocrine factors in the treatment of nervous system diseases.