The role of the insulin-like growth factor family in the nervous system.

Abstract

Insulin-like growth factor-I (IGF-I) and IGF-II are growth factors which promote cell growth and differentiation. IGF signaling involves interaction of IGF-I and IGF-II with type I (IGF-IR) and type II IGF receptors and six IGF binding proteins (IGFBPs). IGF actions are mediated mostly by IGF-IR and modulated by IGFBPs. In this thesis, the expression of IGFBP-5 was studied in the developing rodent nervous system using immunohistochemistry. IGFBP-5 immunoreactivity was detected prenatally in Schwann cells (SCs) and postnatally in SCs and axons of peripheral nerves. IGFBP-5 immunoreactivity was also detected in postnatal cerebellar Purkinje cells as well as neurons within the brain stem. The results, coupled with the known profile of IGF-I expression, demonstrate the colocalization of IGF-I and IGFBP-5 in the developing nervous system. The expression of IGF-I, IGF-IR, and IGFBP-5 was also examined following nerve transection, a model of peripheral nerve injury. After nerve transection, the expression of IGF-I and IGF-IR was increased, especially in the distal nerve stump 7 days after nerve transection, as demonstrated by RNase protection assays. Immunohistochemical studies detected the presence of IGF-I in macrophages and SCs and IGFBP-5 immunoreactivity in SCs. In vitro, IGF-I promoted SC mitogenesis. Northern analysis revealed that SCs express IGF-IR and IGFBP-5. IGF-I treatment increased the intensity of IGFBP-5 by protecting IGFBP-5 from proteolysis. Finally, the possible role of the IGF-I family of proteins in SC differentiation was tested. Addition of 1 mM 8-bromo cAMP or growth on a Matrigel matrix induced differentiation of SC. IGF-I enhanced both cAMP and Matrigel matrix-induced SC differentiation as determined by the morphological criteria and expression of myelin proteins. The expression of IGFBP-5 during SC differentiation was also studied. Both cAMP and Matrigel treatment enhanced IGFBP-5 expression as measured by immunoblotting procedures and Northern analysis. Collectively, the SC response to IGF-I depends on the stage of development. The regulation of IGFBP-S expression suggested it may modulate the actions of IGF-I during SC development.