The generation of neurons in the adult mammalian brain requires the activation of quiescent neural stem cells (NSCs). This activation and the sequential steps of neuron formation from NSCs are regulated by a number of stimuli, which include growth factors. Insulin-like growth factor-I (IGF-I) exert pleiotropic effects, regulating multiple cellular processes depending on their concentration, cell type, and the developmental stage of the animal. Although IGF-I expression is relatively high in the embryonic brain its levels drop sharply in the adult brain except in neurogenic regions, i.e., the hippocampus (HP) and the subventricular zone-olfactory bulb (SVZ-OB). By contrast, the expression of IGF-IR remains relatively high in the brain irrespective of the age of the animal. Evidence indicates that IGF-I influences NSC proliferation and differentiation into neurons and glia as well as neuronal maturation including synapse formation. Furthermore, recent studies have shown that IGF-I not only promote adult neurogenesis by regulating NSC number and differentiation but also by influencing neuronal positioning and migration as described during SVZ-OB neurogenesis. In this article we will revise and discuss the actions reported for IGF-I signaling in a variety of in vitro and in vivo models, focusing on the maintenance and proliferation of NSCs/progenitors, neurogenesis, and neuron integration in synaptic circuits.

The specific actions of insulin-like growth factor-I (IGF-I) and the role of brain-derived IGF-I during hippocampal neurogenesis have not been fully defined. To address the influence of IGF-I on the stages of hippocampal neurogenesis, we studied a postnatal/adult global Igf-I knockout (KO) mice (Igf-I 2/2) and a nervous system Igf-I conditional KO (Igf-I D/D ). In both KO mice we found an accumulation of Tbr2 1 -intermediate neuronal progenitors, some of which were displaced in the outer granule cell layer (GCL) and the molecular layer (ML) of the dentate gyrus (DG). Similarly, more ectopic Ki671 -cycling cells were detected. Thus, the GCL was disorganized with significant numbers of Prox1 1 -granule neurons outside this layer and altered morphology of radial glial cells (RGCs). Dividing progenitors were also generated in greater numbers in clonal hippocampal stem cell (HPSC) cultures from the KO mice. Indeed, higher levels of Hes5 and Ngn2, transcription factors that maintain the stem and progenitor cell state, were expressed in both HPSCs and the GCL-ML from the Igf-I D/D mice. To determine the impact of Igf-I deletion on neuronal generation in vivo, progenitors in Igf-I 2/2 and Igf-I 1/1 mice were labeled with a GFPexpressing vector. This revealed that in the Igf-I 2/2 mice more GFP 1 -immature neurons were formed and they had less complex dendritic trees. These findings indicate that local IGF-I plays critical roles during postnatal/adult hippocampal neurogenesis, regulating the transition from HPSCs and progenitors to mature granule neurons in a cell stage-dependent manner. STEM CELLS 2016;34:2194-2209 SIGNIFICANCE STATEMENTThere is evidence that systemic insulin-like growth factor-I (IGF-I) promotes neuronal maintenance in the postnatal/adult hippocampus. Other studies have suggested the implication of locally-produced IGF-I in the modulation of adult hippocampal neurogenesis in vivo but this concept was not demonstrated. We present novel findings showing that brain IGF-I directs the generation of granule neurons from neural stem cells in the postnatal/adult mouse hippocampus. We also show that the regulation of gene expression and cycling cell number by IGF-I may be part of the mechanisms involved in these actions.