IGF‐I promotes neuronal migration and positioning in the olfactory bulb and the exit of neuroblasts from the subventricular zone

Abstract

While insulin-like growth factor-I (IGF-I) supports neuronal and glial differentiation in the CNS, it is largely unknown whether IGF-I also influences neuronal migration and positioning. We show here that the pattern of olfactory bulb (OB) layering is altered in Igf-I (-/-) mice. In these animals, Tbr1(+)-glutamatergic neurons are misplaced in the mitral cell layer (ML) and the external plexiform layer (EPL). In addition, there are fewer interneurons in the glomerular layer and the EPL of the Igf-I (-/-) mice, and fewer newborn neurons are incorporated into the OB from the forebrain subventricular zone (SVZ). Indeed, neuroblasts accumulate in the postnatal/adult SVZ of Igf-I (-/-) mice. Significantly, the positioning of Tbr1(+)-cells in a primitive ML is stimulated by IGF-I in cultured embryonic OB slices, an effect that is partially repressed by the phosphoinositide 3-kinase (PI3K) inhibitor. In OB cell cultures, IGF-I increases the phosphorylation of disabled1 (P-Dab1), an adaptor protein that is a target of Src family kinases (SFK) in the reelin signalling pathway, whereas reduced P-Dab1 levels were found in Igf-I (-/-) mice. Neuroblast migration from the rostral migratory stream (RMS) explants of postnatal Igf-I (-/-) was similar to that from Igf-I (+/+) explants. However, cell migration was significantly enhanced by IGF-I added to the explants, an effect that was repressed by PI3K and SFK inhibitors. These findings suggest that IGF-I promotes neuronal positioning in the OB and support a role for IGF-I in stimulating neuroblast exit from the SVZ into the RMS, thereby promoting the incorporation of newly formed neurons into the OB.

Endocannabinoids Regulate the Migration of Subventricular Zone-Derived Neuroblasts in the Postnatal Brain

“…Cell adhesion molecules (CAMs), such as neural cell adhesion molecule (NCAM) (Ono et al, 1994;Hu et al, 1996), matrix metalloproteinases (Bovetti et al, 2007;Murase et al, 2008), the ephrin family of receptor tyrosine kinases (Conover et al, 2000;Anton et al, 2004), and growth factors such, as BDNF (Chiaramello et al, 2007), hepatocyte growth factor (Garzotto et al, 2008), glial cell line-derived neurotrophic factor (Paratcha et al, 2006), vascular endothelial growth factor (Zhang et al, 2003), and IGF-1 (Hurtado-Chong et al, 2009), can regulate neuroblast migration. Many of these molecules have the potential to crosstalk to endocannabinoid (eCB) signaling pathways in cells.…”

Regulation of Temporal and Spatial Organization of Newborn GnRH Neurons by IGF Signaling in Zebrafish

“…Our findings in zebrafish may also explain previous findings made in the mouse model. While Igf-1 Ϫ/Ϫ mice exhibited misplaced glutamergic neurons of the mitral cell layers in the olfactory bulb (Hurtado-Chong et al, 2009), mice with deleted IGF1R or the p85␣ regulatory subunit of PI3K in GnRH neurons only (under the control of the GnRH1 promoter) showed a normal number and spatial distribution of GnRH1 neurons, although they exhibited differences in GnRH morphology (AcostaMartínez et al, 2009;Divall et al, 2010).…”

Regulation of Basal and Injury-Induced Fate Decisions of Adult Neural Precursor Cells: Focus on SOCS2 and Related Signalling Pathways

“…Shh is a chemoattractant cue extrinsic to the neuroblast that guides migration to the olfactory bulb. Neurotrophic growth factor signalling is also important for migration, in particular insulin-like growth factor (IGF-1) null mice show an abundance of neuroblasts in the SVZ that have failed to migrate to the olfactory bulb [57]. Guidance cues from EphB2/ephrin-B2 pathways also enable formation of the chain migration from the SVZ to the olfactory bulb [58].…”