The History of the Insulin-Like Growth Factor System.

The growth hormone (GH)-insulin-like growth factor (IGF) cascade is central to the regulation of growth and metabolism. This article focuses on the history of the components of the IGF system, with an emphasis on the peptide hormones, IGF-I and -II, their cell surface receptors, and the IGF binding proteins (IGFBPs) and IGFBP proteases that regulate the availability of the peptide hormones for interaction with their receptors in relevant target tissues. We describe landmark events in the evolution of the somatomedin hypothesis, including evidence that has become available from experiments at the molecular and cellular levels, whole animal and tissue-specific gene knockouts, studies of cancer epidemiology, identification of prismatic human cases, and short- and long-term clinical trials of IGF-I therapy in humans. In addition, this new evidence has expanded our clinical definition of GH insensitivity (GHI) beyond growth hormone receptor mutations (classic Laron syndrome) to include conditions that cause primary IGF deficiency by impacting post-receptor signal transduction, IGF production, IGF availability to interact with the IGF-I receptor (IGF-1R), and defects in the IGF-1R, itself. We also discuss the clinical aspects of IGFs, from their description as insulin-like activity, to the use of IGF-I in the diagnosis and treatment of GH deficiency, and to the use of recombinant human IGF-I for therapy of children with GHI.

The imprinted Igf2-Igf2r axis is critical for matching placental microvasculature expansion to fetal growth.

In all eutherian mammals, growth of the fetus is dependent upon a functional placenta, but whether and how the latter adapts to putative fetal signals is currently unknown. Here, we demonstrate, through fetal, endothelial, hematopoietic, and trophoblast-specific genetic manipulations in the mouse, that endothelial and fetus-derived IGF2 is required for the continuous expansion of the feto-placental microvasculature in late pregnancy. The angiocrine effects of IGF2 on placental microvasculature expansion are mediated, in part, through IGF2R and angiopoietin-Tie2/TEK signaling. Additionally, IGF2 exerts IGF2R-ERK1/2-dependent pro-proliferative and angiogenic effects on primary feto-placental endothelial cells ex vivo. Endothelial and fetus-derived IGF2 also plays an important role in trophoblast morphogenesis, acting through Gcm1 and Synb. Thus, our study reveals a direct role for the imprinted Igf2-Igf2r axis on matching placental development to fetal growth and establishes the principle that hormone-like signals from the fetus play important roles in controlling placental microvasculature and trophoblast morphogenesis.

Autocrine IGF2 programmes ß-cell plasticity under conditions of increased metabolic demand.

When exposed to nutrient excess and insulin resistance, pancreatic ß-cells undergo adaptive changes in order to maintain glucose homeostasis. The role that growth control genes, highly expressed in early pancreas development, might exert in programming ß-cell plasticity in later life is a poorly studied area. The imprinted Igf2 (insulin-like growth factor 2) gene is highly transcribed during early life and has been identified in recent genome-wide association studies as a type 2 diabetes susceptibility gene in humans. Hence, here we investigate the long-term phenotypic metabolic consequences of conditional Igf2 deletion in pancreatic ß-cells (Igf2ßKO) in mice. We show that autocrine actions of IGF2 are not critical for ß-cell development, or for the early post-natal wave of ß-cell remodelling. Additionally, adult Igf2ßKO mice maintain glucose homeostasis when fed a chow diet. However, pregnant Igf2ßKO females become hyperglycemic and hyperinsulinemic, and their conceptuses exhibit hyperinsulinemia and placentomegalia. Insulin resistance induced by congenital leptin deficiency also renders Igf2ßKO females more hyperglycaemic compared to leptin-deficient controls. Upon high-fat diet feeding, Igf2ßKO females are less susceptible to develop insulin resistance. Based on these findings, we conclude that in female mice, autocrine actions of ß-cell IGF2 during early development determine their adaptive capacity in adult life.

Roles of insulin-like growth factor II in regulating female reproductive physiology.

The number of growth factors involved in female fertility has been extensively studied, but reluctance to add essential growth factors in culture media has limited progress in optimizing embryonic growth and implantation outcomes, a situation that has ultimately led to reduced pregnancy outcomes. Insulin-like growth factor II (IGF-II) is the most intricately regulated of all known reproduction-related growth factors characterized to date, and is perhaps the predominant growth factor in human ovarian follicles. This review aims to concisely summarize what is known about the role of IGF-II in follicular development, oocyte maturation, embryonic development, implantation success, placentation, fetal growth, and in reducing placental cell apoptosis, as well as present strategies that use growth factors in culture systems to improve the developmental potential of oocytes and embryos in different species. Synthesizing the present knowledge about the physiological roles of IGF-II in follicular development, oocyte maturation, and early embryonic development should, on the one hand, deepen our overall understanding of the potential beneficial effects of growth factors in female reproduction and on the other hand support development (optimization) of improved outcomes for assisted reproductive technologies.

IGF2 drives formation of ileal neuroendocrine tumors in patients and mice.

By the strictest of definitions, a genetic driver of tumorigenesis should fulfill two criteria: it should be altered in a high percentage of patient tumors, and it should also be able to cause the same type of tumor to form in mice. No gene that fits either of these criteria has ever been found for ileal neuroendocrine tumors (I-NETs), which in humans are known for an unusual lack of recurrently mutated genes, and which have never been detected in mice. In the following report, we show that I-NETs can be generated by transgenic RT2 mice, which is a classic model for a genetically unrelated disease, pancreatic neuroendocrine tumors (PNETs). The ability of RT2 mice to generate I-NETs depended upon genetic background. I-NETs appeared in a B6AF1 genetic background, but not in a B6 background nor even in an AB6F1 background. AB6F1 and B6AF1 have identical nuclear DNA but can potentially express different allelic forms of imprinted genes. This led us to test human I-NETs for loss of imprinting, and we discovered that the IGF2 gene showed loss of imprinting and increased expression in the I-NETs of 57% of patients. By increasing IGF2 activity genetically, I-NETs could be produced by RT2 mice in a B6 genetic background, which otherwise never developed I-NETs. The facts that IGF2 is altered in a high percentage of patients with I-NETs and that I-NETs can form in mice that have elevated IGF2 activity, define IGF2 as the first genetic driver of ileal neuroendocrine tumorigenesis.

LncRNA TUG1 regulates proliferation and apoptosis by regulating miR-148b/IGF2 axis in ox-LDL-stimulated VSMC and HUVEC.

Vascular smooth muscle cell (VSMC) accumulation and endothelial cell dysfunction are associated with pathogenesis of atherosclerosis. Long noncoding RNA taurine up-regulated gene 1 (TUG1) has been reported to play an important role in cardiovascular diseases, including atherosclerosis. However, the regulatory mechanism underlying TUG1 in atherosclerosis is far from understood. VSMC and human umbilical vein endothelial cells (HUVEC) stimulated by oxidized low-density lipoprotein (ox-LDL) were used as cellular model of atherosclerosis. Cell proliferation and apoptosis were detected by CCK-8, flow cytometry and Western blot. The expression levels of TUG1, microRNA (miR)-148b and insulin-like growth factor 2 (IGF2) were measured by quantitative real-time polymerase chain reaction or Western blot. The target association among TUG1, miR-148b and IGF2 was determined by luciferase reporter assay and RNA immunoprecipitation. The expression of TUG1 was increased in ox-LDL-treated VSMC and HUVEC. Silence of TUG1 inhibited proliferation and promoted apoptosis in ox-LDL-treated VSMC but induced proliferation promotion and apoptosis inhibition in HUVEC stimulated by ox-LDL. miR-148b was a target of TUG1 and its knockdown reversed the effect of TUG1 silence on proliferation and apoptosis of VSMC and HUVEC challenged by ox-LDL. IGF2 was a target of miR-148b and miR-148b regulated proliferation and apoptosis in ox-LDL-treated VSMC and HUVEC by targeting IGF2. TUG1 promoted IGF2 protein expression by sponging miR-148b. TUG1 knockdown attenuated ox-LDL-induced injury through regulating proliferation and apoptosis of VSMC and HUVEC by miR-148b/IGF2 axis, providing a novel mechanism for pathogenesis of atherosclerosis.

The Neglected Insulin: IGF-II, a Metabolic Regulator with Implications for Diabetes, Obesity, and Cancer.

When originally discovered, one of the initial observations was that, when all of the insulin peptide was depleted from serum, the vast majority of the insulin activity remained and this was due to a single additional peptide, IGF-II. The IGF-II gene is adjacent to the insulin gene, which is a result of gene duplication, but has evolved to be considerably more complicated. It was one of the first genes recognised to be imprinted and expressed in a parent-of-origin specific manner. The gene codes for IGF-II mRNA, but, in addition, also codes for antisense RNA, long non-coding RNA, and several micro RNA. Recent evidence suggests that each of these have important independent roles in metabolic regulation. It has also become clear that an alternatively spliced form of the insulin receptor may be the principle IGF-II receptor. These recent discoveries have important implications for metabolic disorders and also for cancer, for which there is renewed acknowledgement of the importance of metabolic reprogramming.

Effect of Dexmedetomidine-Mediated Insulin-Like Growth Factor 2 (IGF2) Signal Pathway on Immune Function and Invasion and Migration of Cancer Cells in Rats with Ovarian Cancer.

BACKGROUND The aim of this study was to explore the effect of dexmedetomidine (DEX)-mediated insulin-like growth factor 2 (IGF2) signal pathway on immune function and cancer cell invasion and migration in rats with ovarian cancer. MATERIAL AND METHODS Forty rats with ovarian cancer were divided into 4 groups: model group, and low dose (0.2 µg/kg/hour DEX), medium dose (1.0 µg/kg/hour DEX), and high dose (5.0 µg/kg/hour DEX) DEX groups. In addition, 10 Fischer344 rats were selected as a normal group. Human NUTU-19 poorly differentiated epithelial ovarian cancer cell line cells were divided into 4 groups: a blank group and low dose, medium dose, and high dose DEX NUTU-19 groups. RESULTS Compared with the normal group, in the other groups the serum interleukin (IL)-2 and interferon gamma (INF-γ) levels, CD4⁺ and CD8⁺ percentages, CD4⁺/CD8⁺ ratio, and transformation rate of splenic lymphocytes were decreased, and the serum tumor necrosis factor alpha (TNF-alpha) level, IGF2, insulin-like growth factor 1 receptor (IGF1R), insulin receptor substrate 1 (IRS1) mRNA, and protein expressions in ovarian tissue were increased (all P<0.05). Results in the DEX groups compared with model group were the opposite of those in the other groups compared with normal group (all P<0.05). Compared with the blank group, in the other groups the proliferation, invasion, and migration of ovarian cancer cells were reduced significantly (all P<0.05). Compared with the low dose DEX NUTU-19 group, in the high dose DEX NUTU-19 group the invasion and migration of ovarian cancer cells weakened significantly (both P<0.05). CONCLUSIONS A certain dose of DEX can effectively inhibit IGF2 signal pathway activation to improve the immune function of rats with ovarian cancer, inhibiting the invasion and migration of ovarian cancer cells.

IGF-2 Preprograms Maturing Macrophages to Acquire Oxidative Phosphorylation-Dependent Anti-inflammatory Properties.

Recent investigations revealed that macrophages could be trained with an altered responsiveness, raising the possibility of combating autoimmune diseases by imparting anti-inflammatory capabilities to these cells. While investigating the effect of mesenchymal stem cells on experimental autoimmune encephalomyelitis (EAE), we found a critical role of insulin-like growth factor 2 (IGF-2) in training macrophages to become anti-inflammatory during their maturation. IGF-2 exerts its effects by preprogramming maturing macrophages to commit oxidative phosphorylation (OXPHOS). IGF-2-preprogrammed macrophages maintained the mitochondrial complex V activities even upon pro-inflammation stimulation, thus enabling an elevated programmed death-ligand 1 (PD-L1) expression. PD-L1 neutralization abolished the beneficial effect of IGF-2 on EAE. Furthermore, adoptive transfer of IGF-2-preprogrammed macrophages to EAE mice increased Tregs and alleviated the diseases. Our results demonstrate that shaping macrophage responsiveness by IGF-2 is effective in managing inflammatory diseases, and the OXPHOS commitment can be preset to determine the anti-inflammatory fate of macrophages.

MicroRNA 615-3p Inhibits the Tumor Growth and Metastasis of NSCLC via Inhibiting IGF2.

MicroRNAs are essential regulators of cancer-associated genes at the posttranscriptional level, and their expression is altered in cancer tissues. Herein we sought to identify the regulation of miR-615-3p in NSCLC progression and its mechanism. miR-615-3p expression was significantly downregulated in NSCLC tissue compared to control normal tissue. Exogenous overexpression of miR-615-3p inhibited the growth and metastasis of NSCLC cells. In addition, the in vivo mouse xenograft model showed that overexpression of miR-615-3p inhibited NSCLC growth and lung metastasis, whereas decreased expression of miR-615-3p caused an opposite outcome. Furthermore, we revealed that insulin-like growth factor 2 (IGF2) expression was negatively correlated with the miR-615-3p level in NSCLC specimens, and IGF2 knockdown mimicked the effect of miR-615-3p inhibition on NSCLC cell proliferation, migration, and invasion. In addition, overexpression of IGF2 rescued the inhibition of miR-615-3p in NSCLC cells. Together, our results indicated that miR-615-3p played important roles in the regulation of NSCLC growth and metastasis by targeting IGF2.

Children's biobehavioral reactivity to challenge predicts DNA methylation in adolescence and emerging adulthood.

A growing body of research has documented associations between adverse childhood environments and DNA methylation, highlighting epigenetic processes as potential mechanisms through which early external contexts influence health across the life course. The present study tested a complementary hypothesis: indicators of children's early internal, biological, and behavioral responses to stressful challenges may also be linked to stable patterns of DNA methylation later in life. Children's autonomic nervous system reactivity, temperament, and mental health symptoms were prospectively assessed from infancy through early childhood, and principal components analysis (PCA) was applied to derive composites of biological and behavioral reactivity. Buccal epithelial cells were collected from participants at 15 and 18 years of age. Findings revealed an association between early life biobehavioral inhibition/disinhibition and DNA methylation across many genes. Notably, reactive, inhibited children were found to have decreased DNA methylation of the DLX5 and IGF2 genes at both time points, as compared to non-reactive, disinhibited children. Results of the present study are provisional but suggest that the gene's profile of DNA methylation may constitute a biomarker of normative or potentially pathological differences in reactivity. Overall, findings provide a foundation for future research to explore relations among epigenetic processes and differences in both individual-level biobehavioral risk and qualities of the early, external childhood environment.

Insulin growth factor 2 (IGF2) as an emergent target in psychiatric and neurological disorders. Review.

Insulin-like growth factor 2 (IGF2) is abundantly expressed in the central nervous system (CNS). Recent evidence highlights the role of IGF2 in the brain, sustained by data showing its alterations as a common feature across a variety of psychiatric and neurological disorders. Previous studies emphasize the potential role of IGF2 in psychiatric and neurological conditions as well as in memory impairments, targeting IGF2 as a pro-cognitive agent. New research on animal models supports that upcoming investigations should explore IGF2's strong promising role as a memory enhancer. The lack of effective treatments for cognitive disturbances as a result of psychiatric diseases lead to further explore IGF2 as a promising target for the development of new pharmacology for the treatment of memory dysfunctions. In this review, we aim at gathering all recent relevant studies and findings on the role of IGF2 in the development of psychiatric diseases that occur with cognitive problems.

The ZBED6-IGF2 axis has a major effect on growth of skeletal muscle and internal organs in placental mammals.

A single nucleotide substitution in the third intron of insulin-like growth factor 2 (IGF2) is associated with increased muscle mass and reduced subcutaneous fat in domestic pigs. This mutation disrupts the binding of the ZBED6 transcription factor and leads to a threefold up-regulation of IGF2 expression in pig skeletal muscle. Here, we investigated the biological significance of ZBED6-IGF2 interaction in the growth of placental mammals using two mouse models, ZBED6 knock-out (Zbed6-/-) and Igf2 knock-in mice that carry the pig IGF2 mutation. These transgenic mice exhibit markedly higher serum IGF2 concentrations, higher growth rate, increased lean mass, and larger heart, kidney, and liver; no significant changes were observed for white adipose tissues. The changes in body and lean mass were most pronounced in female mice. The phenotypic changes were concomitant with a remarkable up-regulation of Igf2 expression in adult tissues. Transcriptome analysis of skeletal muscle identified differential expression of genes belonging to the extracellular region category. Expression analysis using fetal muscles indicated a minor role of ZBED6 in regulating Igf2 expression prenatally. Furthermore, transcriptome analysis of the adult skeletal muscle revealed that this elevated expression of Igf2 was derived from the P1 and P2 promoters. The results revealed very similar phenotypic effects in the Zbed6 knock-out mouse and in the Igf2 knock-in mouse, showing that the effect of ZBED6 on growth of muscle and internal organs is mediated through the binding site in the Igf2 gene. The results explain why this ZBED6 binding site is extremely well conserved among placental mammals.

IGF2 stimulates fetal growth in a sex- and organ-dependent manner.

BackgroundInsulin-like growth factor 2 (IGF2) is a key determinant of fetal growth, and the altered expression of IGF2 is implicated in fetal growth disorders and maternal metabolic derangements including gestational diabetes. Here we studied how increased levels of IGF2 in late pregnancy affect fetal growth.MethodsWe employed a rat model of repeated intrafetal IGF2 administration in late pregnancy, i.e., during GD19-GD21, and measured the consequences on fetal organ weight and expression of insulin/IGF-axis components.ResultsIGF2 treatment tended to increase fetal weight, but only weight increase of the fetal stomach reached significance (+33±9%; P<0.01). Sex-dependent data analysis revealed a sexual dimorphism of IGF2 action. In male fetuses, IGF2 administration significantly increased fetal weight (+13±3%; P<0.05) and weight of fetal stomach (+42±10%; P<0.01), intestine (+26±5%; P<0.05), liver (+13±4%; P<0.05), and pancreas (+25±8%; P<0.05). Weights of heart, lungs, and kidneys were unchanged. In female fetuses, IGF2 increased only stomach weight (+26±9%; P<0.05). Furthermore, gene expression of insulin/IGF axis in the heart, lungs, liver, and stomach was more sensitive toward IGF2 treatment in male than in female fetuses.ConclusionData suggest that elevated circulating IGF2 in late pregnancy predominantly stimulates organ growth of the digestive system, and male fetuses are more susceptible toward the IGF2 effects than female fetuses.

Recent advances on the role of long non-coding RNA H19 in regulating mammalian muscle growth and development.

As one of the first identified long non-coding RNAs (lncRNAs), H19 plays a wide range of roles in vivo, including not only as a tumor suppressor and oncogene involved in disease process, but also as a regulator of growth and development of multiple tissues in mammalian embryos. The function of H19 in muscles (both skeletal and cardiac muscle) draws widespread attention due to the following two reasons. On one hand, H19 promotes myogenic differentiation and myogenesis of skeletal muscle satellite cells (SMSCs) via regulating Igf2 in cis. On the other hand, H19 also modulates the target genes in trans, including sponging let-7, miR-106 or miR-29 to mediate myocyte glucose uptake, cardiomyocyte proliferation and tendon repair, as well as promote embryonic development and muscle regeneration through binding to MBD1 as a chromatin modifier. In this review, we summarize the role of H19 in mammalian muscles, which will provide a reference for further research to unveil the molecular mechanism of muscle growth and development.

Insulin-like growth factor signaling regulates developmental trajectory associated with diapause in embryos of the annual killifish Austrofundulus limnaeus.

Annual killifishes exhibit a number of unique life history characters including the occurrence of embryonic diapause, unique cell movements associated with dispersion and subsequent reaggregation of the embryonic blastomeres, and a short post-embryonic life span. Insulin-like growth factor (IGF) signaling is known to play a role in the regulation of metabolic dormancy in a number of animals but has not been explored in annual killifishes. The abundance of IGF proteins during development and the developmental effects of blocking IGF signaling by pharmacological inhibition of the insulin-like growth factor I receptor (IGF1R) were explored in embryos of the annual killifish Austrofundulus limnaeus Blocking of IGF signaling in embryos that would normally escape entrance into diapause resulted in a phenotype that was remarkably similar to that of embryos entering diapause. IGF-I protein abundance spikes during early development in embryos that will not enter diapause. In contrast, IGF-I levels remain low during early development in embryos that will enter diapause II. IGF-II protein is packaged at higher levels in escape-bound embryos compared with diapause-bound embryos. However, IGF-II levels quickly decrease and remain low during early development and only increase substantially during late development in both developmental trajectories. Developmental patterns of IGF-I and IGF-II protein abundance under conditions that would either induce or bypass entrance into diapause are consistent with a role for IGF signaling in the regulation of developmental trajectory and entrance into diapause in this species. We propose that IGF signaling may be a unifying regulatory pathway that explains the larger suite of characters that are associated with the complex life history of annual killifishes.

Synovial chondromatosis of the temporomandibular joint: Immunohistochemical examinations regarding the role of insulin-like growth factors and their binding proteins in the etiology of this disease.

Synovial chondromatosis (SC) is a benign disease of the joints without a known cause. It sometimes affects the temporomandibular joint (TMJ) and is accompanied by pain, swelling, malocclusion, and crepitation. It has been divided into three stages by Milgram and is supposed to originate from the synovia and cartilage of a joint (Milgram, 1977b). The aim of this study was to examine an involvement of the insulin-like growth factors (IGF-I/-II) and their binding proteins (IGFBP-1 to -6) in the etiology of this disease. Therefore 23 specimen of SC from 16 patients were immunohistochemically stained and microscopically examined. Staining was assessed semiquantitatively: negative (-), weakly positive ((+)), moderately positive (+), strongly positive (++) and very strongly positive (+++). It could be seen that especially the chondro- and fibrocytes and the synovia showed positive staining for almost all IGFs and IGFBPs. The underlying tissue, consisting of connective tissue or chondroid matrix, was stained as well but more weakly so. We conclude that the IGF/IGFBP system seems to contribute to the pathogenesis of SC, especially IGF-I and -II, and their effects enhancing binding protein 5.

IGF2 knockdown in two colorectal cancer cell lines decreases survival, adhesion and modulates survival-associated genes.

Increased expression of insulin-like growth factor 2 (IGF2) is found in tumors of colorectal cancer (CRC) patients exhibiting a gained region on chromosome 11q15 and is implicated in poor patient survival. This study analyzes in vitro phenotypic- and gene expression changes associated with IGF2 shRNA-mediated knockdown. Initially, doxycycline inducible IGF2 knockdown cell lines were generated in the CRC cell lines SW480 and LS174T. The cells were analyzed for changes in proliferation, cell cycle, apoptosis, adhesion, and invasion. Expression profiling analysis was performed, and, for a subset of the identified genes, expression was validated by qRT-PCR and Western blot. IGF2 knockdown inhibited cell proliferation in both cell lines induced G1 cell cycle blockade and decreased adhesion to several extracellular matrix proteins. Knockdown of IGF2 did not alter invasiveness in SW480 cells, while a slight increase in apoptosis was seen only in the LS174T cell line. Knockdown of IGF2 in SW480 deregulated 58 genes, several of which were associated with proliferation and cell-cell/cell-ECM contacts. A subset of these genes, including CDK2, YAP1, and BIRC5 (Survivin), are members of a common network. This study supports the concept of direct autocrine/paracrine tumor cell activation through IGF2 and a shows role of IGF2 in CRC proliferation, adhesion and, to a limited extent, apoptosis.

Insulin-like growth factor 2 rescues aging-related memory loss in rats.

Aging is accompanied by declines in memory performance, and particularly affects memories that rely on hippocampal-cortical systems, such as episodic and explicit. With aged populations significantly increasing, the need for preventing or rescuing memory deficits is pressing. However, effective treatments are lacking. Here, we show that the level of the mature form of insulin-like growth factor 2 (IGF-2), a peptide regulated in the hippocampus by learning, required for memory consolidation and a promoter of memory enhancement in young adult rodents, is significantly reduced in hippocampal synapses of aged rats. By contrast, the hippocampal level of the immature form proIGF-2 is increased, suggesting an aging-related deficit in IGF-2 processing. In agreement, aged compared to young adult rats are deficient in the activity of proprotein convertase 2, an enzyme that likely mediates IGF-2 posttranslational processing. Hippocampal administration of the recombinant, mature form of IGF-2 rescues hippocampal-dependent memory deficits and working memory impairment in aged rats. Thus, IGF-2 may represent a novel therapeutic avenue for preventing or reversing aging-related cognitive impairments.

IGF-2/IGF-1R signaling has distinct effects on Sox1, Irx3, and Six3 expressions during ES cell derived-neuroectoderm development in vitro.

Insulin-like growth factors (IGFs) are involved in growth and tissue development, including diseases such as type-2 diabetes and cancers. However, their roles in lineage specification, especially in early mammalian neural development, are poorly understood. Here, we analyzed the protein expression of IGF-2 in early mouse embryo, and it was preferentially detected in anterior mesodermal tissue, adjacent to the neural plate. We utilized a self-organizing neural tissue culture system and analyzed the direct effect of IGF-2 on the general neural marker Sox1. Interestingly, using recombinant IGF-2 and a chemical inhibitor of its receptor (IGF-1R), we found that the IGF-2/IGF-1R pathway positively regulated Sox1 expression in embryonic stem (ES) cell-derived neural tissue. Furthermore, to visualize the expression patterns of other neural markers, we used reporter ES cell lines and we found that the IGF-2/IGF-1R signaling upregulated the expression of the posterior neural marker Irx3. In contrast, the anterior neural marker Six3 was downregulated by IGF-2/IGF-1R signaling. Together, our results demonstrate that IGF-2/IGF-1R signaling has different effects on neural marker expression, which may influence the early regional identity of ES cell-derived neural tissues.