Biochemical and Morphometric Analyses Show that Myelination in the Insulin-like Growth Factor 1 Null Brain Is Proportionate to Its Neuronal Composition

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Abstract
To elucidate the role of insulin-like growth factor 1 (IGF1) in the normal development of brain myelination, we used behavioral, biochemical, and histological analyses to compare the myelination of brains from Igf1−/− and wild-type (WT) littermate mice. The studies were conducted at postnatal day 40, at which time the Igf1−/− mice weighed ∼66% less than wild-type mice. However, theIgf1−/− brain weight was only reduced by ∼34%. Formal neurological testing showed no sign of central or peripheral myelinopathy inIgf1−/− mice. Myelin composition was not significantly different, and myelin concentration, normalized to brain weight or protein, was equal inIgf1−/− and WT mice. Likewise, concentrations of myelin-specific proteins (MBP, myelin proteolipid protein, MAG, and 2′,3′-cyclic nucleotide,3′-phosphodiesterase) were not significantly different inIgf1−/− and WT mice. The myelin-associated lipids galactocerebroside and sulfatide were modestly reduced in Igf1−/− brains. Regional oligodendrocyte populations and myelin staining patterns were comparable in Igf1−/− and WT brains, with the notable exception of the olfactory system. TheIgf1−/− olfactory bulb was profoundly reduced in size and was depleted of mitral neurons and oligodendrocytes, and its efferent tracts were depleted of myelin. In summary, this study shows that myelination of theIgf1−/− brain is proportionate to its neuronal composition. Where projection neurons are preserved despite the deletion of IGF1, as in the cerebellar system, oligodendrocytes and myelination are indistinguishable from wild type. Where projection neurons are depleted, as in the olfactory bulb, oligodendrocytes are also depleted, and myelination is reduced in proportion to the reduced projection neuron mass. These data make a strong case for the primacy of axonal factors, not including IGF1, in determining oligodendrocyte survival and myelination.