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. 2008 Aug 7;149(12):5958–5962. doi: 10.1210/en.2008-0920

Expanding the Mind: Insulin-Like Growth Factor I and Brain Development

A Joseph D'Ercole 1, Ping Ye 1
PMCID: PMC2613055  PMID: 18687773

Abstract

Signaling through the type 1 IGF receptor (IGF1R) after interaction with IGF-I is crucial to the normal brain development. Manipulations of the mouse genome leading to changes in the expression of IGF-I or IGF1R significantly alters brain growth, such that IGF-I overexpression leads to brain overgrowth, whereas null mutations in either IGF-I or the IGF1R result in brain growth retardation. IGF-I signaling stimulates the proliferation, survival, and differentiation of each of the major neural lineages, neurons, oligodendrocytes, and astrocytes, as well as possibly influencing neural stem cells. During embryonic life, IGF-I stimulates neuron progenitor proliferation, whereas later it promotes neuron survival, neuritic outgrowth, and synaptogenesis. IGF-I also stimulates oligodendrocyte progenitor proliferation although inhibiting apoptosis in oligodendrocyte lineage cells and stimulating myelin production. These pleiotropic IGF-I activities indicate that other factors provide instructive signals for specific cellular events and that IGF-I acts to facilitate them. Studies of the few humans with IGF-I and/or IGF1R gene mutations indicate that IGF-I serves a similar role in man.

IGF-I SIGNALING through the type 1 IGF receptor (IGF1R) is essential for brain development (1,2,3). Evidence of IGF-I actions on neural cell development comes from a wide variety of in vitro and in vivo experimental data, the latter predominantly derived from rodent studies. IGF-I stimulates 1) proliferation of neural progenitors and possibly pluripotent neural stem cells (NSC), 2) survival of neurons and oligodendrocytes, and 3) differentiation of neurons, including neuritic outgrowth and synaptogenesis, and of oligodendrocytes, including expression of myelin gene proteins and myelination. As a result of these events, brain growth is increased with IGF-I overexpression and reduced as a result of decreased IGF-I signaling. Little evidence supporting comparable actions for IGF-II is available. Although much less information is available in man, individuals with IGF-I gene deletions or mutations that result in severe deficits in IGF-I expression are microcephalic and mentally retarded (4). There have been no reports of humans born with mutations leading to absent IGF1R expression, but two children with heterozygous IGF1R mutations leading to reduced IGF1R expression exhibited microcephaly and mild mental retardation and/or learning disorders, and another with an IGF1R mutation leading to reduced IGF-I affinity exhibited altered behavioral characteristics (5,6).

IGF-I is widely expressed in the central nervous system, often exhibiting peak expression that is temporally and spatially related to brain development (3). IGF-II also is expressed in the brain and surrounding structures, but its expression is more restricted. The IGF1R is ubiquitously expressed in all neural cells including NSC. A number of IGF-binding proteins (IGFBPs) are expressed during brain development, but their expression is variable, generally occurring at specific times and locales. The widespread and developmentally associated expression of each component of the IGF system, i.e. IGF, IGF1R, and IGFBPs, argues that IGFs act during brain development locally near its sites of expression in an autocrine and/or paracrine fashion. This argument is further supported by the experimental findings: 1) IGF-I- and IGF1R-null mutant mice, including those with mutations conditionally restricted to neural cells, exhibit brain growth retardation and 2) brain IGF-I overexpression without elevations in circulating IGF-I leads to brain overgrowth. Nonetheless, because IGFs are transported across the blood-brain barrier and peripherally administered IGF-I exerts actions in the brain (7), it is likely that circulating IGF-I influences brain development and biology, at least, at later developmental stages when circulating IGF-I levels are higher and brain IGF-I expression is lower.

Overall Brain Growth

Manipulations of the mouse genome leading to changes in the expression of IGF-I or IGF1R significantly alter brain growth (8). Brain IGF-I overexpression, regardless of whether it is accompanied by widespread somatic IGF-I overexpression, results in an increased brain size. The magnitude of the overgrowth depends on the magnitude and the developmental time of IGF-I overexpression. When nestin genomic regulatory elements direct IGF-I overexpression at peak levels early in embryonic brain development, brain weight is increased by 10–20% from late in gestation onward (9). IGF-I transgene expression directed by the metallothionein-I promoter begins in late gestation, increases postnatally, and continues at a high level throughout life. As a consequence, brain overgrowth is first significant at about 2 wk of life and increases asymptotically throughout life. The magnitude appears to depend upon the degree of transgene overexpression, with some lines of mice exhibiting brain weights that are increased as much as 80%. IGF-I-null mutant mice exhibit retardation of both body and brain growth, such that in young adulthood, body and brain weights are reduced by 65–75 and 29–38%, respectively (10,11). In these mice, the hippocampus is most retarded (by 46%), followed by the cerebellum (by 35%), cerebral cortex (by 30%), and diencephalon and brainstem (by 20–22%). Ablation of IGF1R expression also results in body and brain growth retardation. At the time of birth, when these mice die, body weights are about 45% of normal (12,13). The degree of brain weight retardation, however, was not quantified. In other mice with heterozygous deletion of the IGF1R gene specifically in neural progenitors, brain weights are reduced by about 40% at 90 d of age and are not accompanied by body growth retardation (unpublished data).

Neural Stem Cells

Although there is substantial evidence that IGF-I stimulates the proliferation of progenitors that become neurons, oligodendrocytes, and astroglia, there is conflicting in vitro evidence as to whether IGF-I influences pluripotent NSC. NSC are generally defined as having the capacity to divide and to differentiate into each neural lineage (14). In the embryo, NSC reside in the neuroepithelium, a layer of cells lining the lateral ventricles. In later development and in the adult, proliferating NSC persist in the subventricular zone (SVZ) and in the subgranular layer of the dentate gyrus in the hippocampus. Evidence suggesting that IGF-I influences NSC includes 1) IGF-I and the IGF1R as well as some IGFBPs are expressed in cultured NSC derived from both embryos and adults (3,16) and 2) in response to IGF-I, and often in concert with other growth factors, cultured NSC derived from a variety of embryonic (16,17,18) and adult (19) sources proliferate as NSC (16,17,18) or proceed toward specific lineages, such as neurons (19) or oligodendrocytes (20).

The lack of a unique marker for NSC makes it difficult to distinguish IGF-I in vivo stimulation of proliferation of NSC from that of fate-committed neural progenitors. Analysis of transgenic (Tg) mice that overexpress IGF-I under the control of nestin genomic regulatory elements indicate that IGF-I contributes to the embryonic development of multiple neural lineages in a sequence that mimics normal development. Nestin, an intermediate filament protein, is expressed in NSC, radial glia, and neuron progenitors. Nestin promoter-driven IGF-I overexpression results in an increased portion of proliferating progenitors in the ventricular zone (VZ) and SVZ (9), and in turn, an increased number of neuron progenitors in the intermediate zone and neurons in the cortical plate of the embryonic d 14 (E14) telencephalon. Later in life, these mice also exhibit an increase number of glia. Figure 1 depicts two alternative models of the nature of IGF-I-IGF1R actions in embryonic brain development. Detailed evaluations of early neural proliferation in the cortex of these mice show that IGF-I shortens the duration of the cell cycle (due solely to a decrease in G1 phase) and increases the number of cells that reenter the cell cycle (22). Whether the proliferating VZ and SVZ cells are pluripotent or fate-restricted precursors, or both, remains uncertain. The finding that IGF1R signaling appears to be required for the proliferation of pluripotent human embryonic stem cells (23) argues that IGF-I also may expand NSC. Taken together, these findings argue that IGF-I stimulates the proliferation of neural progenitors, some of which differentiate into neurons in the embryo, whereas others become glia later in development.

Figure 1.

Figure 1

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Alternative models of IGF1R signaling in neural progenitors. A, IGF1R signaling asymmetric division of NSC. B, IGF1R stimulation of radial glia proliferation leading to a replicate radial glial cell and a neuron progenitor. In this model, radial glia also give rise to astroglia and oligodendrocyte, albeit at a later time in development. IZ, Intermediate zone.

Neurogenesis

IGF-I influences the entire process of neurogenesis beginning with the proliferation of neuron progenitors and extending through neuritic growth, synaptogenesis, and neuron elimination by apoptosis. IGF-I stimulation of neuron progenitor proliferation in vitro is well documented (2,3,24). Neuron number has been found to be increased in all IGF-I-overexpressing mice when it has been evaluated (8). Whether promotion of proliferation or survival is the predominant mechanism for these increases depends upon the developmental time and magnitude of overexpression. When IGF-I is overexpressed during the time of peak neurogenesis (E11–E17), there is a dramatic increase in the number of proliferating neuron progenitors (9), such that at E16, the volume and cell number in the cortical plate are increased by more than 50%. At this embryonic time in cortical plate, neurons are the predominant cell type, and apoptosis is rare (25); thus, the increase in cell number reflects IGF-I-stimulated proliferation. IGF-I promotion of neuron survival, however, clearly contributes to postnatal increases in neuron number, and these antiapoptotic actions of IGF-I have been documented in two lines of IGF-I-overexpressing mice, where significant decreases in the number of apoptotic neurons have been demonstrated in the cerebellum (26,27) and in the cerebral cortex (25).

IGF-I also appears to differentially influence specific brain regions (28). In all mutant mice so evaluated, the neuron number in the hippocampus and the dentate gyrus, as well as their respective sizes, are most influenced by alterations in IGF-I signaling. Other differential effects also have been observed in the cerebral cortex. For example, when IGF-I is overexpressed during embryogenesis, neuron number in the motor cortex is relatively more increased than in the somatosensory cortex, and cortical layers also are disproportionately increased (layer I > V > II/III > VI > IV). The reasons for these differential effects are not known, but greater IGF-I responsiveness in some progenitors seems a reasonable possibility.

Differentiation of neurons

Both in vitro and in vivo studies have demonstrated the capacity of IGF-I to stimulate neuronal differentiation. Studies demonstrating IGF-I stimulation of neuritic outgrowth were among the first showing IGF-I actions on neural cells (29). Later IGF-I was shown to increase dendrite growth in cultured neonatal Purkinje cells (30) and to increase the number of pyramidal cell dendrites and their branching in somatosensory cortical explants (31). In cultured hippocampal neurons, IGF-I stimulates the assembly of axonal growth cones (32). Studies of Tg and mutant mice are consistent with these findings. Detailed studies in IGF-I-overexpressing mice show that IGF-I stimulates increases in synapse number in the hippocampus (33) and the hypoglossal nucleus (34) and, thus, by inference increases in neurites. More specifically, in the developing hippocampus, IGF-I overexpression stimulates an increase in synapse number that is greater than the increase in neuron number. The natural process of synapse elimination, however, is not altered by IGF-I overexpression, and therefore, by adulthood, the synapse to neuron ratio is normal, although both synapse and neuron number are increased. Consistently, IGF-I-null mutants demonstrate a decrease in dendrite length and complexity in the cortex (35). The sensorineural hearing loss observed in IGF-I-null mutants (36), thus, could result from alterations in axon growth and dendritic arborization. Importantly, sensorineural hearing loss has been described in humans with IGF-I or IGF1R gene mutations (4,5).

IGF-I also influences the size of neuron soma. A reduction in pyramidal neuron soma size has been observed in IGF-I-null mutant mice (35). This is accompanied by an increase in cell density and, thus, a decrease in neuropil, the area not occupied by neuron cell bodies or soma. By inference, the decrease in neuropil indicates that neuritic outgrowth is diminished. A marked increase in cell density, necessarily accompanied by decreased neuropil, also has been observed in the embryonic brain of IGF1R-null mutant mice (13). In contrast, the somatosensory cortex of IGF-I-overexpressing mice exhibit increased neuron cell size, decreased neuron density, and an increase in the area occupied by neuropil (37). When medulla nuclei were evaluated in a different line of IGF-I-overexpressing mice, increases in the size of motor neuron soma were observed in some nuclei as well as evidence of increased neuritic outgrowth (38). Taken together, these findings suggest specificity in IGF-I neuron growth-promoting actions.

Oligodendrocyte Development

Signaling through the IGF1R is essential for normal oligodendrocyte development and normal myelination. Oligodendrocyte lineage development and myelination, however, occurs in the absence of IGF1R signaling, but oligodendrocyte number is reduced and myelination is diminished. A number of studies of cultured oligodendrocyte progenitor cells (OPC) demonstrate that IGF1R signaling promotes survival and augments differentiation and myelin formation (39,40,41). In mixed rat glial cultures and in a nontransformed OPC line, called OL-1, IGF-I stimulates increases in OPC number but only a modest increase in DNA synthesis, whereas exposure to caspase inhibitors produce increases in cell number nearly comparable to those stimulated by IGF-I (41,42). These studies suggest, therefore, that IGF-I is primarily a survival factor for OPC. In these cultures, IGF-I also stimulates oligodendrocyte lineage progression, manifested by an increased expression of myelin-associated protein genes and in the numbers of cell processes.

The conclusions drawn from studies of cultured OPC are supported by analysis of mutant mice. IGF-I overexpression has dramatic effects on myelination. In IGF-I Tg mice with expression directed either by metallothionein-I or myelin basic protein promoters, total brain myelin content is markedly elevated (43,44). Oligodendrocyte number was shown to be increased in the former Tg mice. This was accompanied by a disproportionate increase in the expression of myelin-associated gene proteins (45), suggesting IGF-I directly stimulates the expression of these genes. The phenotypic result of these IGF-I actions is myelination of axons with smaller diameters, which are not myelinated in wild-type mice, and an increase in the number of myelin layers wrapping around each axon (46).

Because mice with a global deletion of the IGF1R gene die perinatally before the time of oligodendrocyte maturation (12), two lines of mice with IGF1R-null mutations restricted either to OPC or to mature oligodendrocytes were generated using a cre/lox system (47). In one line, termed IGF1Rpre-oligo-ko mice, recombination is directed by the promoter for Olig1, a helix-loop-helix transcription factor that is expressed in early OPC and is key to oligodendrocyte progenitor differentiation. In the other line, IGF1Roligo-ko mice, Cre expression is directed by the promoter for proteolipid protein (PLP), a major myelin protein expressed in mature oligodendrocytes. In IGF1Rpre-oligo-ko mice, brain regions composed primarily of oligodendrocyte lineage cells, such as corpus callosum and anterior commissure, showed marked decreases in volume (by 35–55%) and cell number (by 54–70%) at 2 and 6 wk of postnatal age, respectively. IGF1Roligo-ko mice exhibited less marked reductions that were most apparent at older ages, consistent with the later ablation of IGF1R signaling in mature oligodendrocytes (Fig. 2). The number of oligodendrocyte precursors was decreased by about 60% in IGF1Rpre-oligo-ko mice, resulting in a 56% decrease in mature oligodendrocytes. These studies of IGF1R-deficient mice make it clear that IGF1R signaling is required for normal oligodendrocyte development and myelination (Fig. 2).

Figure 2.

Figure 2

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Representative photomicrographs of PLP mRNA in situ hybridization of corpus callosum (CC) and myelin basic protein (MBP) immunocytochemical staining (ICC) of brainstem in 6-wk-old IGF1Roligo-KO mice and their littermate controls. CTX, Cerebral cortex. Note that the number of PLP mRNA-expressing oligodendrocytes and the amount of myelin basic protein are much less in the IGF1Roligo-KO mice.

Given the above findings, it is not surprising that IGF-I-null mutants exhibit alterations of oligodendrocyte development and myelination. The alterations in myelination, however, are ameliorated through the course of postnatal development. IGF-I-null mutant mice exhibit much greater size reductions in oligodendrocyte-rich brain regions (about 70% decreases in the corpus callosum and anterior commissure area, compared with 38% reduction in brain size) with comparable reductions in oligodendrocyte number and an increase in the percentage of unmyelinated axons (10). Despite a reduced total number of oligodendrocytes and their progenitors, the concentrations of myelin-associated proteins and their mRNAs, although low during early development, become normal in early adulthood (11,48). Increased IGF-II expression in the brains of IGF-I-null mutants likely exerts a compensatory stimulation of myelin production (11). Consistently, myelination is reduced when IGFBP-1, an inhibitor of both IGF-I and IGF-II actions, is overexpressed (45,49). A deficiency in myelination also may contribute to the sensorineural hearing loss (36) observed in IGF-I-null mutants. To date, no deficits in myelination have been described in humans with IGF-I or IGF1R gene defects (4,5,6). Detailed studies aimed at myelination in these rare patients, however, have not been performed. Because patients were evaluated later than the first several years of life, myelination deficits may have been ameliorated over time, as they are in IGF-I-null mutant mice (11,48).

Astrocyte Development

A number of lines of evidence point to the involvement of IGF-I in glial and astrocyte development. Cultured neonatal rat astroglia proliferate in response to IGF-I and epidermal growth factor (EGF) (15,50), and a combination of both is synergistic (50). As is the case in other types of cultured neural cells, antibodies against IGF-I blocks proliferative responses to both IGF-I and EGF, indicating that EGF actions are at least in part mediated by stimulating IGF-I synthesis. In mice overexpressing IGF-I from early in embryonic development, glia number is increased in the postnatal cerebral cortex to a magnitude similar to that of neurons, suggesting that the increased progenitor proliferation during embryonic development ultimately facilitates glial, as well as neuron, differentiation (9) (Fig. 1). When IGF-I overexpression is driven in astrocytes under the control of a glial fibrillary acid protein promoter, astrocyte number is increased by 56% when assessed in the dentate gyrus (21). The astrocyte soma size also is increased, indicating IGF-I autocrine actions. Because astrocyte-specific IGF-I overexpression also leads to increased neuron and oligodendrocyte number, paracrine actions also occur.

Conclusions

Normal brain growth and development is dependent on IGF1R signaling, predominately through its interaction with IGF-I. Given the pleiotropic responses stimulated by IGF-I-IGF1R signaling, its actions appear to be largely determined by the signaling mechanisms in place in specific neural cells at precise times in development. It is unlikely that IGF-I provides the primary signal that triggers/initiates intrinsic developmental programs, such as directing stem cell differentiation toward a single lineage. Rather, it appears that IGF-I facilitates or augments specific processes in concert with other factors that provide instructive signals. The site of IGF-I expression also appears important to IGF1R signaling. When overexpressed in neurons prenatally, neuron and glial number are most influenced, whereas postnatal neuron expression has major effects on oligodendrocyte number and myelination (8). When overexpressed in astrocytes, the site of increased IGF-I after a wide variety of injuries, the astrocyte itself is a major target, but each neural lineage is affected (21). A major challenge, thus, is to elucidate the mechanisms that govern the response of specific neural cells to IGF1R signaling.

Acknowledgments

We thank Dr. Ali Calikoglu for review of this manuscript.

Footnotes

This work was supported by National Institutes of Health (NIH) R01 Grants HD008299, NS038891, and NS048868 and NIH Training Grant T32 DK007129.

Disclosure Statement: The authors have nothing to disclose.

First Published Online August 7, 2008

Abbreviations: E14, Embryonic d 14; EGF, epidermal growth factor; IGFBP, IGF-binding protein; IGF1R, type 1 IGF receptor; NSC, neural stem cells; OPC, oligodendrocyte progenitor cells; SVZ, subventricular zone; Tg, transgenic; VZ, ventricular zone.

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