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Molecular Neurobiology

, Volume 13, Issue 3, pp 227–255 | Cite as

The role of the insulin-like growth factors in the central nervous system

  • A. Joseph D’Ercole
  • Ping Ye
  • Ali Suha Calikoglu
  • Gabriel Gutierrez-Ospina
Article

Abstract

Increasing evidence strongly supports a role for insulin-like growth factor-I (IGF-I) in central nervous system (CNS) development. IGF-I, IGF-II, the type IIGF receptor (the cell surface tyrosine kinase receptor that mediates IGF signals), and some IGF binding proteins (IGFBPs; secreted proteins that modulate IGF actions) are expressed in many regions of the CNS beginningin utero. The expression pattern of IGF system proteins during brain growth suggests highly regulated and developmentally timed IGF actions on specific neural cell populations. IGF-I expression is predominantly in neurons and, in many brain regions, peaks in a fashion temporally coincident with periods in development when neuron progenitor proliferation and/or neuritic outgrowth occurs. In contrast, IGF-II expression is confined mainly to cells of mesenchymal and neural crest origin. While expression of type I IGF receptors appears ubiquitous, that of IGFBPs is characterized by regional and developmental specificity, and often occurs coordinately with peaks of IGF expression.

In vitro IGF-I has been shown to stimulate the proliferation of neuron progenitors and/or the survival of neurons and oligodendrocytes, and in some cultured neurons, to stimulate function. Transgenic (Tg) mice that overexpress IGF-I in the brain exhibit postnatal brain overgrowth without anatomic abnormality (20–85% increases in weight, depending on the magnitude of expression). In contrast, Tg mice that exhibit ectopic brain expression of IGFBP-1, an inhibitor of IGF action when present in molar excess, manifest postnatal brain growth retardation, and mice with ablated IGF-I gene expression, accomplished by homologous recombination, have brains that are 60% of normal size as adults. Taken together, these in vivo studies indicate that IGF-I can influence the development of most, if not all, brain regions, and suggest that the cerebral cortex and cerebellum are especially sensitive to IGF-I actions. IGF-I’s growth-promoting in vivo actions result from its capacity to increase neuron number, at least in certain populations, and from its potent stimulation of myelination. These IGF-I actions, taken together with its neuroprotective effects following CNS and peripheral nerve injury, suggest that it may be of therapeutic benefit in a wide variety of disorders affecting the nervous system.

Index Entries

Insulin-like growth factors insulin-like growth factor receptors insulin-like growth factor binding proteins brain transgenic mice 

Abbreviations

BBB

blood-brain barrier

CNS

central nervous system

E

embryonic day

EGF

epidermal growth factor

EAE

experimental autoimmune encephalomyelitis

FGF

fibroblast growth factor

GH

growth hormone

ISHH

in situ hybridization histochemistry

IRS

insulin receptor substrate

IGF-I and IGF-II

insulin-like growth factor-I and-II

IGFBPs

insulin-like growth factor binding proteins

MBP

myelin basic protein

MT-1

metallothionein-1

P

postnatal day

PLP

proteolipid protein

Tg

transgenic

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Copyright information

© Humana Press Inc 1996

Authors and Affiliations

  • A. Joseph D’Ercole
    • 1
  • Ping Ye
    • 1
  • Ali Suha Calikoglu
    • 1
  • Gabriel Gutierrez-Ospina
    • 1
  1. 1.Department of Pediatrics CB# 7220The University of North CarolinaChapel Hill

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