Insulin-like growth factor-I (ICF-I), a 70-amino acid-protein structurally
similar to insulin, promotes cell proliferation and differentiation in mult
iple tissues. Most of its effects are mediated by the Type I IGF receptor (
IGF-IR), a heterotetramer that has tyrosine kinase activity and phosphoryla
tes insulin receptor substrates (IRS-l and 2) which leads to the activation
of two downstream signaling cascades: the MAP kinase and the phosphatidyli
nositol 3-kinase (P3K) cascades. The growth-promoting effects of IGF-I are
prominent in the nervous system, qualifying this molecule as a neurotrophin
. Although the primary regulator of IGF-I expression is growth hormone (GH)
, the developmental expression of IGF-I in various tissues precedes that of
GH, supporting an independent role of IGF-I in embryonic and fetal life [1
]. This review will examine the effect of IGF-l on central nervous system (
CNS) development. The specialized structure of the CNS is the product of a
complex series of biological events which result from the interaction betwe
en the cells' genetic program and environmental influences. CNS development
begins in the embryo with dorsal ectodermal cell proliferation to form the
neural plate, and, with its closure, the neural tube, followed by the rapi
d division of pluripotential cells, their migration to the periphery of the
neural tube, and differentiation into neural or glial cells. During the la
tter stages, cells form special structures such as nuclei, ganglia, cerebra
l cortical layers, and they also develop a network with their cytoplasmic e
xtensions, neurites. Many more cells and connections are generated in fetal
life than are found in the mature organism. This excessive production of s
ome cell groups and neurites may compensate for tissue loss due to various
injuries, and their selective elimination also constitutes an efficient way
to organize the architecture of the CNS. This elimination is believed to b
e accomplished by apoptosis. The cells' intrinsic program for development i
ncludes the expression of various genes at different times. Environmental i
nfluences, such as extracellular matrix (ECM) molecules that attract or rep
el cells, afferent inputs, and target-derived diffusible molecules modify a
nd modulate cellular behavior. ICF-I is among the molecules which affect se
veral steps involved in development.