Review
Neurodevelopmental effects of insulin-like growth factor signaling

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Abstract

Insulin-like growth factor (IGF) signaling greatly impacts the development and growth of the central nervous system (CNS). IGF-I and IGF-II, two ligands of the IGF system, exert a wide variety of actions both during development and in adulthood, promoting the survival and proliferation of neural cells. The IGFs also influence the growth and maturation of neural cells, augmenting dendritic growth and spine formation, axon outgrowth, synaptogenesis, and myelination. Specific IGF actions, however, likely depend on cell type, developmental stage, and local microenvironmental milieu within the brain. Emerging research also indicates that alterations in IGF signaling likely contribute to the pathogenesis of some neurological disorders. This review summarizes experimental studies and shed light on the critical roles of IGF signaling, as well as its mechanisms, during CNS development.

Highlights

► IGF signaling exerts pleiotropic actions on all major neural cell types in the CNS. ► IGF signaling acts critically on virtually at every stage of CNS development. ► IGF actions depend on the cell types, developmental stages, and microenvironment.

Introduction

Experimental evidence accumulated during the past two decades has convincingly established an essential role for insulin-like growth factor (IGF) signaling in the normal growth and development of the central nervous system (CNS). IGF-I and IGF-II, two members of the IGF system, share homology with each other and with proinsulin. In developing brain, IGF signaling exerts pleiotropic actions on all major neural cell types [including neural stem cells (NSCs), lineage restricted neural precursor cells (NPCs), post-mitotic neurons, oligodendrocytes and astrocytes]. IGFs act to promote the proliferation, maturation, survival, and/or growth of neural cells, predominantly, if not exclusively, by interacting with the type 1 IGF receptor (IGF1R). The biological nature of the actions, however, appears to depend on the specific cell types in place, the local microenvironment, and the particular stage of development. IGF signaling also appears to influence specific biological processes in concert with additional neural signaling, which may provide primary instructive signals to steer NSC toward a specific cell lineage during early development.

Our current knowledge of IGF signaling in the developing brain comes predominantly from a wide variety of in vitro and in vivo experimental studies, the latter primarily derived from studies of mutant mouse models. Nevertheless, individual patients with mutation(s) in the igf-I gene (Camacho-Hubner et al., 1999, Woods et al., 1997) or in the igf1r gene (Abuzzahab et al., 2003, Kruis et al., 2010, Okubo et al., 2003, Wallborn et al., 2010, Woods et al., 1997) are found to be associated with severe body growth failure, microcephaly, and mental retardation, strongly arguing for a similar role for IGF signaling during CNS development in humans. Recent literature also has established that many of growth-related phenomena in neural cells, such as neurogenesis (Gage, 2002, Kelsch et al., 2010, Ming and Song, 2011), axon remodeling and de novo synaptogenesis (Bruel-Jungerman et al., 2007, Butefisch, 2006, Carmichael, 2003, Cayre et al., 2009, Gogolla et al., 2007), persist throughout adult life. In parallel, IGFs and their receptors are steadily expressed in the adult brain in a spatial-specific pattern, albeit at relatively lower levels, and are thought to have a significant role in the pathogenesis of several growth-related neurological disorders. In this article, we will review the actions of IGF signaling on brain neural cells with a focus on IGF actions during prenatal and early postnatal life.

Section snippets

Overview of the IGF system

The IGF system is traditionally comprised of IGF-I, IGF-II, the IGF1R, the type 2 IGF receptor (IGF2R), and IGF binding proteins (IGFBPs). The growth-promoting actions of IGF-I and IGF-II are predominantly, if not exclusively, mediated by the IGF1R. The receptor binding and biological activities of IGFs are modulated by IGFBPs. At least 10 IGFBPs, including 6 high-affinity IGFBPs and 4 low-affinity IGFBPs, have been identified.

In mice, the actions of IGF–IGF1R signaling appear to be

Ontogeny of IGF-I, IGF-II, IGF1R and IGF2R in brain

In the developing CNS, IGFs and IGF receptors are widely expressed in a tempo-spatial specific manner. Table 1 summarizes the expression of IGF-I, as well as that of IGF-II, IGF1R and IGF2R, in the major brain areas during perinatal development and in adult (Ayer-le et al., 1991, Bartlett et al., 1992, Bondy and Chin, 1991, Bondy and Lee, 1993, Bondy, 1991, Cavallaro et al., 1993, Dugas et al., 2008, Folli et al., 1994, Hawkes and Kar, 2003, Kar et al., 1993, Lee et al., 1993, Logan et al., 1994

IGF-I actions in the CNS

The development of the mammalian brain occurs along specific stages, including neurulation, neurogenesis, differentiation into neurons and glia, neuronal migration, dendritic and axon outgrowth, naturally occurring cell death, synaptogenesis, and myelination. The time course for these stages differs among species. In general, there is a caudal-to-rostral gradient in the time course of these developmental stages for individual regions in a given brain. The growth promoting actions of IGF-I–IGF1R

IGF-II actions

In cultures, IGF-II exerts actions on the development and growth of neural cells in a manner that is similar to that of IGF-I. Genetic studies also clearly demonstrate that IGF-II has an important role in growth during early development. Global ablation of IGF-II gene expression in igf-II KO mice results in a marked retardation in body growth (Baker et al., 1993, DeChiara et al., 1990, Liu et al., 1993) and in brain growth, leading to a 24% reduction in brain weight at postnatal day 8 (Lehtinen

Signaling through IGF1R

Most IGF growth actions, if not all, are mediated by IGF1R. Direct interaction of IGF with the IGF1R in CNS neural cells is essential for the normal neural development and the proper brain cytoarchitecture, as summarized in the sections above. While our understanding of IGF intracellular signaling has been significantly advanced in recent years, the intracellular signaling pathways that mediate each of IGF actions in the CNS remain to be precisely elucidated. Fig. 5 depicts largely simplified

IGF actions in the human CNS

IGF-I, IGF-II, IGF1R and IGF2R are widely expressed in human brain and CSF (Carlsson-Skwirut et al., 1986, Chesik et al., 2006, Connor et al., 1997, De Keyser et al., 1994, Mashayekhi et al., 2010, Wilczak et al., 2000, Wilczak and De, 1997). There is, however, little information available about the actions of IGF signaling in human neural development. Several individuals with a mutation in the igf-I gene or the igf1r gene have been reported. The available findings from these patients are

Injuries and neurological disorders

Emerging data have shown that the expression of IGF system proteins is significantly altered in a variety of brain injuries and neurological disorders (Popken et al., 2005), which are characterized by a marked loss of neural cells due to either increased cell death and/or reduced proliferation. Given that IGF signaling has a critical role in proliferation, survival and differentiation of neural cells, IGFs (primarily IGF-I) have been implicated in the pathogenesis of many neurological disorders

Conclusion

Over the past 20 years or more, literature illustrates that IGF signaling plays critical roles in the growth and development of the CNS at virtually every stage of development. IGF-I increases the survival of pre-implantation embryos reaching the blastocyst stage through its anti-apoptotic actions and through its ability to protect against reactive oxygen species. Both IGF-I and IGF-II promote NSC/NPC proliferation during development, and IGF-I accelerates neuronogenesis by reducing G1 phase

Acknowledgments

Data from our laboratories reported in this work were partially supported by NIH Grants RO1 NS038891, RO1 NS048868, and Multiple Sclerosis Society Grant PP1531.

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