Insulin‐like growth factor type 1 receptor signaling in the cells of oligodendrocyte lineage is required for normal in vivo oligodendrocyte development and myelination

Abstract

Insulin-like growth factor-I (IGF-I) has been shown to be a potent agent in promoting the growth and differentiation of oligodendrocyte precursors, and in stimulating myelination during development and following injury. To definitively determine whether IGF-I acts directly on the cells of oligodendrocyte lineage, we generated lines of mice in which the type 1 IGF receptor gene (igf1r) was conditionally ablated either in Olig1 or proteolipid protein expressing cells (termed IGF1R pre-oligo-ko and IGF1R oligo-ko mice, respectively). Compared to wild type mice, IGF1R pre-oligo-ko mice had a decreased volume (by 35% to 55 %) and cell number (by 54% to 70%) in the corpus callosum (CC) and anterior commissure at 2 and 6 weeks of age, respectively. IGF1R oligo-ko mice by 25 weeks of age also showed reductions, albeit less marked, in CC volume and cell number. Unlike astrocytes, the percentage of NG2 + oligodendrocyte precursors was decreased by ~13% in 2-week-old IGF1R pre-oligo-ko mice, while the percentage of CC1 + mature oligodendrocytes was decreased by ~24% in 6-week-old IGF1R pre-oligo-ko mice and ~25% in 25-week-old IGF1R oligo-ko mice. The reduction in these cells is apparently a result of decreased proliferation and increased apoptosis. These results indicate that IGF-I directly affects oligodendrocytes and myelination in vivo via IGF1R, and that IGF1R signaling in the cells of oligodendrocyte lineage is required for normal oligodendrocyte development and myelination. These data also provide a fundamental basis for developing strategies with the potential to target IGF-IGF1R signaling pathways in oligodendrocyte lineage cells for the treatment of demyelinating disorders.

Myelination and mTOR

“…Although deletion of each of these proteins, or their cognate receptors, impaired OL myelination to some extent (Cellerino, Carroll, Thoenen, & Barde, 1997; Furusho, Ishii, & Bansal, 2017; Joseph D'Ercole & Ye, 2008; Kahn et al, 1999; Vondran, Clinton‐Luke, Honeywell, & Dreyfus, 2010; Ye, Li, Richards, DiAugustine, & D'Ercole, 2002; Zeger et al, 2007), it is unclear whether they are both necessary and sufficient to drive OL myelination, analogous to NRG1 type III in the PNS. The precise physiological cellular sources of these growth factors and the signals controlling their production and release are currently being elucidated.…”

Maturation-dependent sensitivity of oligodendrocyte lineage cells to apoptosis: implications for normal development and disease

“…This is a result of both slower proliferation and increased apoptosis. 22 IGF-1 is a factor studied for its regeneration potential as a therapeutic agent after brain injury. Conversely, CNTF (ciliary neurotrophic factor) is an example of an OL differentiation factor that fails on its own to stimulate re-myelination in vivo after injury.…”

Directing traffic in neural cells: determinants of receptor tyrosine kinase localization and cellular responses

“…Finally, late endosomes fuse with the lysosomal compartment (Tjelle et al (Mason et al 2003;Zeger et al 2007); Neuronal development (Schlueter et al 2007) ErbB4…”