Cellular pattern of type-I insulin-like growth factor receptor gene expression during maturation of the rat brain: Comparison with insulin-like growth factors I and II

Abstract

Insulin-like growth factors have a number of potent trophic effects on cultured neurat tissue and most if not all of these effects appear to be mediated by the type-I insulin-like growth factor receptor. In order to establish the identity of cell types expressing this receptor in the rat centrat nervous system during development and maturity, we have used in situ hybridization to map sites of type-I insulin-like growth factor receptor mRNA synthesis in the developing and adult rat brain. In order to identify possible local sources of peptide ligands for this receptor, we have also mapped the sites of insulin-like growth factors I and II mRNA synthesis in paratlel brain sections. From early development onward, there is a uniform and stable pattern of type-I insulin-like growth factor receptor gene expression in all neuro epithelial cell lineages, in which regional variations reflect primarily differences in cell density. In addition to this generatized pattern, during late postnatal development, high levels of type-I insulin-like growth factor receptor gene expression are found in specific sets of sensory and cerebellar projection neurons in conjunction with abundant insulin-like growth factor-I gene expression in these same neurons. While insulin-like growth factor-I expression is confined to the principal neurons in each system, receptor mRNA is also found in local interneurons. In the cerebrat cortex and hippocampal formation, type-I insulin-like growth factor receptor mRNA and insulin-like growth factor-I are concentrated in different cell populations: receptor mRNA is abundant in pyramidal cells in Ammon's horn, in granule cells in the dentate gyrus, and in pyramidal cells in lamina VI of the cerebrat cortex. Insulin-like growth factor-I mRNA is found in isolated medium- to large-sized cells which are rather irregularly distributed throughout the hippocampus and isocortex. In the hypothalamus, receptor mRNA is concentrated in the suprachi asmatic nucleus but is in low abundance elsewhere, including the median eminence, while insulin-like growth factor-I mRNA is not detected in this region at all. Type-I insulin-like growth factor receptor and insulin-like growth factor-II mRNAs are both abundant in choroid plexus, menínges and vascular sheaths from early development to maturity, but insulin-like growth factor-II mRNA is not detected in cells of neuroepithelial origin at any stage of development. This study provides evidence for two fundamentally different patterns of gene expression for the brain type-I insulin-like growth factor receptor. Firstly, there is a relatively stable and uniform level of receptor gene expression shared by all neuroepithelial lineages. This receptor distribution may be the target of circulating insulin-like growth factors, which are secreted into the bloodstream by the liver and into the cerebrospinal fluid by the choroid plexus, and subserve a very basic metabolic or trophic function. Secondly, superimposed upon this apparently constitutive pattern, during the course of postnatal differentiation, specific sets of neurons show high levels of type-I receptor gene expression in conjunction with local insulin-like growth factor-I expression. These findings suggest that there are specific local fields of paracrine and/or autocrine insulin-like growth factor-I action mediated by the type-I receptor in the brain parenchyma.