BIOCHEMICAL AND MORPHOMETRIC ANALYSES SHOW THAT MYELINATION IN THE INSULIN-LIKE-GROWTH-FACTOR-1 NULL BRAIN IS PROPORTIONATE TO ITS NEURONALCOMPOSITION

To elucidate the role of insulin-like growth factor 1 (IGF1) in the no rmal 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 conduct ed at postnatal day 40, at which time the Igf1(-/-) mice weighed simil ar to 66% less than wild-type mice. However, the Igf1(-/-) brain weigh t was only reduced by similar to 34%. Formal neurological testing show ed no sign of central or peripheral myelinopathy in Igf1(-/-) mice. My elin composition was not significantly different, and myelin concentra tion, normalized to brain weight or protein, was equal in Igf1(-/-) an d WT mice. Likewise, concentrations of myelin-specific proteins (MBP, myelin proteolipid protein, MAG, and 2',3'-cyclic nucleotide,3'-phosph odiesterase) were not significantly different in Igf1(-/-) and WT mice . The myelin-associated lipids galactocerebroside and sulfatide were m odestly reduced in Igf1(-/-) brains. Regional oligodendrocyte populati ons and myelin staining patterns were comparable in Igf1(-/-) and WT b rains, with the notable exception of the olfactory system. The Igf1(-/ -) olfactory bulb was profoundly reduced in size and was depleted of m itral neurons and oligodendrocytes, and its efferent tracts were deple ted of myelin. In summary, this study shows that myelination of the Ig f1(-/-) brain is proportionate to its neuronal composition. Where proj ection neurons are preserved despite the deletion of IGF1, as in the c erebellar system, oligodendrocytes and myelination are indistinguishab le from wild type. Where projection neurons are depleted, as in the ol factory bulb, oligodendrocytes are also depleted, and myelination is r educed in proportion to the reduced projection neuron mass. These data make a strong case for the primacy of axonal factors, not including I GF1, in determining oligodendrocyte survival and myelination.