Brain Insulin‐Like Growth Factor‐I Directs the Transition from Stem Cells to Mature Neurons During Postnatal/Adult Hippocampal Neurogenesis

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−/−) and a nervous system Igf‐I conditional KO (Igf‐IΔ/Δ). In both KO mice we found an accumulation of Tbr2+‐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 Ki67+‐ cycling cells were detected. Thus, the GCL was disorganized with significant numbers of Prox1+‐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‐IΔ/Δ mice. To determine the impact of Igf‐I deletion on neuronal generation in vivo, progenitors in Igf‐I−/− and Igf‐I+/+ mice were labeled with a GFP‐expressing vector. This revealed that in the Igf‐I−/− mice more GFP+‐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 The absence of IGF‐I alters the structure and volume of the GCL and the morphology of Nestin+‐RGCs, produces an accumulation and displacement of Tbr2+‐ neuronal progenitor cells and impairs the maturation and positioning of granule neurons (compare bottom versus top images). Our findings suggest that the effects of brain IGF‐I deficiency might be dependent on the upregulation of Hes5 and Ngn2 and the maintenance of cells in cycle, facts that could impair the transition from NSCs to mature granule neurons. Scale bar: 23.9 μm.