• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Cytokine Growth Factor Rev. Author manuscript; available in PMC Apr 1, 2009.
Published in final edited form as:
PMCID: PMC2314671
NIHMSID: NIHMS45387

IGF2: Epigenetic regulation and role in development and disease

Abstract

Insulin-like growth factor II (IGF2) is perhaps the most intricately regulated of all growth factors characterized to date. Its gene is imprinted—only one allele is active, depending on parental origin—and this pattern of expression is maintained epigenetically in almost all tissues. IGF2 activity is further controlled through differential expression of receptors and IGF-binding proteins (IGFBPs) that determine protein availability. This complex and multifaceted regulation emphasizes the importance of accurate IGF2 expression and activity. This review will examine the regulation of the IGF2 gene and what it has revealed about the phenomenon of imprinting, which is frequently disrupted in cancer. IGF2 protein function will be discussed, along with diseases that involve IGF2 overexpression. Roles for IGF2 in sonic hedgehog (Shh) signaling and angiogenesis will also be explored.

Keywords: Insulin-like growth factor, imprinting, angiogenesis, vascular endothelial growth factor, sonic hedgehog

1. Introduction

In the early 1900s, the innovative surgeon Alexis Carrel experimented with maintaining tissues and whole organs in vitro, hoping to advance techniques in organ transplantation. Carrel observed that certain tissue extracts could induce cell proliferation, and he published his findings with this disclaimer:

“Possibly the finding of the activating power of tissue extracts will have no immediate practical application. Nevertheless, it may be indirectly useful by leading to the discovery of some of the factors determining the growth of tissues and of the unknown laws of cell dynamics… [1].”

Carrel was mistaken that this finding would have no practical application—rather, it pioneered the discipline of tissue culture and the widespread use of serum to support in vitro cell growth. He was right, however, that this “activating power” would eventually lead to the discovery of growth factors, many of which were isolated and characterized in the decades that followed. Two of these factors, which were structurally similar to insulin, had many effects on cell growth and differentiation. In 1987, after 30 years of confusing nomenclature, these proteins were designated as insulin-like growth factor I (IGF1) and insulin-like growth factor II (IGF2) (Table 1).

TABLE 1
A brief history of the insulin-like growth factors (IGFs).

The IGFs regulate cell growth and differentiation in many species. The anabolic functions of growth hormone are largely mediated by IGF1, which designates IGF1 as a major determinant of somatic growth [10]. Rare mutations in the human IGF1 gene lead to severe growth inhibition and mental retardation [11]. Igf1-null mice are born at 60% of normal birth weight, and the few that survive to adulthood are less than one-third the size of normal mice [12, 13]. On the other hand, IGF2 is virtually dispensable for post-natal development in mice, since Igf2 expression is almost entirely limited to the embryo in rodents [14]. At birth, Igf2-null mice are also growth-impaired but are otherwise normal, and subsequent growth proceeds at normal rates [13].

These studies support a somewhat redundant role for IGF2; furthermore, its designation as the “second” IGF seems to have relegated it to a lesser role than IGF1. However, IGF2 is the predominant IGF in adult humans (reviewed in [15]), and inappropriate IGF2 expression is implicated in a growing number of diseases (reviewed in [16]). The importance of IGF2 is highlighted by its complex and multifaceted regulation. The gene that codes for IGF2 is imprinted such that only one allele is expressed, depending on parental origin [14]. Besides the intriguing mechanisms that surround its imprinted expression, IGF2 is further modulated by a concert of differentially expressed proteins and receptors that determine IGF availability (reviewed in [17]). This review will examine the complex epigenetic regulation of the IGF2 gene and provide a broad introduction to IGF2 signaling. The ability of IGF2 to stimulate cell proliferation and differentiation will be reviewed, which will lead to a discussion on its involvement in various cancers and other diseases. The angiogenic functions of IGF2 will be addressed, and conclude with a proposal that IGF2 is a key mediator facilitating the angiogenic activity of sonic hedgehog (Shh).

2. The IGF2 gene

2.1 Epigenetic regulation of Igf2

Igf2 is widely expressed during murine embryonic development and is particularly important in placental growth [18]. As with many genes that regulate placental development, Igf2 is imprinted, or expressed monoallelically, and active only on the paternally inherited allele. Igf2 is highly expressed in the mouse embryo, but levels decline dramatically after birth; in adult mice, Igf2 transcripts are detectable only in the choroid plexus and leptomeninges, where expression is biallelic [14]. IGF2 is also imprinted in humans, but is expressed biallelically in the choroid plexus, leptomeninges, and perhaps the developing retina [19]. However, human IGF2 is also expressed in the adult, with transcripts arising from an adult-specific promoter [20]. The corresponding region in the mouse Igf2 gene contains two pseudoexons and what appears to be a remnant of this adult-specific promoter—which may explain why Igf2 expression ceases after birth in mice but not in humans [21].

Almost all known imprinted genes occur in clusters with one or more reciprocally imprinted genes (reviewed in [22]). The mouse Igf2 gene lies on the distal region of chromosome 7 with the oppositely imprinted, non-coding gene H19. Igf2 and H19 share a set of enhancers that act on either gene, depending on parental origin. In eukaryotic DNA, promoters generally harbor regions dense with CpG dinucleotides, which are targets of methylation. These “CpG islands” are often methylated in inactive promoters. On the paternal chromosome, the H19 promoter region is methylated and inactive; this methylation and expression pattern is passed on when cells divide. Because this inheritance of gene expression patterns is achieved without altering the DNA sequence, it is called epigenetic.

The Igf2 promoter is not methylated on the maternal chromosome, so another mechanism must account for silencing Igf2. Several kilobases (kb) upstream of the H19 promoter is a differentially methylated region (DMR) that, when deleted, reactivates Igf2 on the maternal chromosome [23]. This region, also called the imprinting control region (ICR), was found to harbor binding sites for CCCTC binding factor (CTCF), an insulator protein that demarcates active and inactive chromatin domains (reviewed in [24]). Methylation of the CG-rich CTCF binding sequence prevents CTCF binding. Thus, on the paternal chromosome, the DMR/ICR is methylated, CTCF is excluded, and the enhancers act on the Igf2 promoter. Conversely, on the maternal chromosome, CTCF forms a chromatin insulator that blocks the enhancers from activating Igf2 (Figure 1A).

Figure 1
(A) Model of imprinted regulation at the Igf2-H19 locus. Adapted from [25]. (B) Model of allele-specific repression in X chromosome inactivation by CTCF. Adapted from [2628]. DMR: differentially methylated region. Lollipops: methylated CpGs. ...

2.2 Igf2 imprinting as a model of allele-specific repression

Murine Igf2 was the first gene found to be imprinted, and has served as a model of allele-specific gene repression—the most extreme example being X chromosome inactivation, where one X is silenced in each somatic cell of XX female mammals to equalize gene dosage with XY males [29]. Igf2 imprinting and X chromosome inactivation are the most well-studied mechanisms of epigenetic regulation, and the parallels between these mechanisms give insight into the epigenetic alterations that are abundant in cancer.

X chromosome inactivation generally occurs in a random fashion and silences either X; however, in some mammals and in certain tissues of others, the paternal X is always silenced. In either random or imprinted X chromosome inactivation, the X that is destined to be silenced expresses the non-coding Xist RNA, which covers the chromosome and mediates silencing (reviewed in [30]).

Xist lies in a region called the X inactivation center (XIC) along with another noncoding gene, Tsix, is transcribed antisense to Xist and expressed on the active X chromosome [31]. Not long after CTCF was shown to regulate imprinting at the Igf2/H19 locus, a similar mechanism was found at the Xist/Tsix locus. In a region implicated in controlling both random and imprinted X chromosome inactivation, functional methylation-sensitive CTCF binding sites were identified (Figure 1B). This region was later found to contain developmentally specific enhancers [28] and to be differentially methylated in vivo [27]. CTCF has since been demonstrated to control imprinting at several other gene domains, and putative binding sites have been discovered in several other imprinted loci [32]. However, not all imprinted genes contain functional CTCF binding sites. It is proposed that another multifunctional transcription factor, yin yang 1 (YY1), functions as a methylation-sensitive insulator that mediates allele-specific gene activation or silencing at some loci. YY1 has been found to control imprinting at the human SNURF-SNRPN locus within the Prader-Willi syndrome and Angelman syndrome locus, and the PEG3, Gnas, and Nespas genes ([33] and references therein). Interestingly, it was shown recently that YY1 is a cofactor for CTCF in X chromosome inactivation [34]. Because both CTCF and YY1 are ubiquitously expressed, it is possible that tissue- and developmentally-specific imprinting of Igf2 is accomplished through a combination of these factors.

The similarities between Igf2/H19 and Xist/Tsix regulation have additional implications for other regulatory mechanisms that may be aberrant in cancer. The X chromosomes initiate silencing after forming a transient interchromosomal complex (reviewed in [30]). This pairing phenomenon has also been observed with the Igf2/H19 region, in which CTCF mediates interchromosomal colocalization and induces trans effects on a non-homologous chromosome [35]. Interchromosomal pairing may increase the frequency of mitotic recombination, which can account for both heritable and sporadic mutations [36]. Because CTCF mediates interchromosomal pairing of the IGF2/H19 region, it may very well facilitate such mitotic recombination events. X chromosome inactivation has also drawn attention in the field of cancer research with the recent discovery of X-linked tumor suppressor genes; when mutated, these can lead to hemizygosity in males and skewed X inactivation in females (reviewed in [37]). One gene, FOXP3, codes for a forkhead family transcription factor that represses the HER-2/ErbB2 oncogene [38]. Interestingly, the forkhead transcription factors are targets of the PI3-kinase pathway, which is activated by IGF signaling (reviewed in [39]). The other X-linked tumor suppressor, WTX, was frequently inactivated in Wilms’ tumor, a disease also associated with disrupted IGF2 imprinting [40].

X chromosome inactivation can have other implications for Igf2/H19 regulation as well. There is mounting evidence that non-coding (especially antisense) RNAs regulate allele-specific gene expression (reviewed in [30]). Multiple sense and antisense transcripts have been detected in the mouse Igf2 5’ region, and the major antisense transcript, Igf2AS, is paternally expressed and noncoding [41]. An antisense message transcribed from a homologous region near human IGF2 encodes a putative 273-amino acid protein of unknown function [42]. It remains unclear whether IGFAS regulates IGF2 or H19 imprinting; nonetheless, it may have biological importance. In Wilms’ tumor, IGF2AS is highly expressed and demonstrates sporadic loss of imprinting [42, 43]. As stated before, disrupted IGF2 imprinting is implicated in a number of diseases, and can be attributed to increased gene dosage and subsequent increases in IGF2 signaling, which will be discussed in the following section.

3. The IGF2 protein

3.1 IGF system overview

The IGFs signal primarily through the type I IGF receptor (IGF1R), but there is significant crosstalk between the IGF and insulin systems as certain variants of the insulin receptor (IR) have been shown to bind IGFs (Figure 2). The alternatively spliced IR-A isoform, which is expressed predominantly during embryogenesis [44], binds insulin and IGF2 (but not IGF1) with high affinity [45]. IGF2 can also stimulate insulin-like metabolic responses by binding the classical IR-B isoform; furthermore, functional heterodimers can form between IGF1R and the IR isoforms (reviewed in [46]). Thus, tissue-specific effects of insulin and the IGFs may be accomplished through differential expression of the receptors and receptor hybrids. Though IGF1R is activated more efficiently by IGF1 [47], the ability to signal through IR potentially gives IGF2 a broader range of biological functions than IGF1.

Figure 2
Overview of the insulin/IGF system. IR exists in two isoforms: IR-A and IR-B. IR-B is responsible for the classic metabolic responses induced by insulin, and also binds IGF1 and IGF2 with low and intermediate affinity, respectively. IR-A has high affinity ...

IGF2 has high affinity for another receptor, IGF2R, and is its principal ligand (Figure 2). However, IGF2R does not transduce a signal; rather, it serves mainly to limit IGF2 bioavailability by targeting IGF2 for degradation (reviewed in [48]). Interestingly, the IGF2R gene is also imprinted—but it is maternally expressed (reviewed in [16]).

Whereas insulin circulates freely in the bloodstream, the IGFs are found in complexes with the IGF binding proteins (IGFBPs). Six different IGFBPs have been identified, and each binds the IGFs with significantly higher affinity than IGF1R. The expression patterns of the various IGFBPs differ both spatially and temporally, and they have distinct activities (Table 2). Thus, IGFBPs are important modulators of IGF action, availability, and tissue distribution (reviewed in [17]). Differential expression of IGFBPs, as well as differential expression of IGF receptors and receptor hybrids, may govern the cell- and tissue-specific actions of IGFs.

Table 2
IGFBP functions (Adapted from [17])

3.2 IGF2 in cell growth and differentiation

IGF1 and IGF2 are well known for their mitogenic activities. Almost all cell types express IGF1R, so the IGFs can stimulate growth and differentiation in many tissues (reviewed in [49]). Upon binding to IGF1R, the IGFs trigger the receptor tyrosine kinase activity, which leads to phosphorylation of itself and its major substrate, the insulin receptor substrate 1 (IRS-1). Phosphorylated IRS-1 can activate the Ras/Raf/MAPK and PI3-kinase/Akt cascades, and depending on the cell type, stimulate proliferation, differentiation, or both (reviewed in [50]). PI3-kinase activation can lead to anti-apoptotic signals, and components of this pathway are frequently amplified or mutated in cancers (reviewed in [51]).

The role of IGF2 in muscle development has been studied extensively. IGF2 is upregulated early in MyoD-induced in myocyte differentiation, and signals in an autocrine loop to activate PI3-kinase and Akt [52]. IGF2 inhibition leads to reduced expression of MyoD target genes, which suggests that IGF2 is essential for amplifying and maintaining MyoD efficacy [53]. IGF2 is also essential in bone development, where it promotes proliferation and differentiation of bone cells. Down-regulation of IGF2 most likely accounts for the decrease in bone mass observed with cortisol use [54]. Thus, IGF2 has great therapeutic potential in wound and fracture healing.

Growth in the developing mouse embryo is largely governed by IGF2. When a targeted Igf2 deletion is transmitted paternally, mouse embryos inherit only the inactive maternal allele and are born runted [14]. Conversely, IGF2 overexpression, achieved by disrupting the inhibitory Igf2r [55], by deleting H19 [56], or by transactivating Igf2 [57], leads to fetal overgrowth and malformations with characteristics that resemble Beckwith-Wiedemann syndrome (BWS, discussed below).

4. IGF2 and disease

4.1 Loss of IGF2 imprinting

IGF2 is regulated precisely to ensure monoallelic expression in most tissues [19], which emphasizes the importance of gene dosage. Normal development requires accurate expression, and many disorders can be attributed to an abnormally high dose of IGF2 caused by loss of imprinting (LOI). BWS is one such disease, characterized by fetal and neonatal overgrowth, and is often accompanied by an increased risk of childhood cancers (reviewed in [58]). BWS patients almost always have mutations in the chromosome 11p15.5 region, a large cluster of imprinted genes that includes IGF2 and p57KIP2 (Figure 3). Most of these mutations affect imprinting; quite often, biallelic IGF2 expression and H19 methylation are observed (reviewed in [16]). BWS usually occurs sporadically, but in rare familial cases IGF2 LOI may be caused by deletions of the CTCF binding sites in the maternal IGF2/H19 ICR [59, 60].

Figure 3
(A) Normal and (B) BWS gene expression patterns on chromosome 11p15.5. Arrows represent active genes. Lollipops: methylated CpGs. Red octagon: CTCF. Asterisks: point mutations. Filled triangles: translocation breakpoints. Open triangles: deletions. Adapted ...

Disrupted imprinting is perhaps the most common observation in cancer (reviewed in [61]), and IGF2 overexpression is a recurring theme. Wilms’ tumor, a childhood cancer of the kidney, is often associated with defects in the WT1 gene, which encodes a transcriptional repressor of IGF2 [62]. Wilms’ tumor is also associated with mutations in the 11p15.5 region that affect IGF2 imprinting: altered IGF2 expression accounts for nearly 50% of all cases of Wilms’ tumor, and IGF2 LOI is found in the vast majority (90%) of pathological cases [63]. IGF2 LOI has also been observed in many other cancers. Both benign and malignant breast lesions show biallelic IGF2 expression, and altered imprinting of IGF2 is has been identified in hepatoblastoma, lung cancer, cervical carcinoma, rhabdomyosarcoma, choriocarcinoma, and testicular cancer ([64] and references therein).

The epigenetic mutations associated with cancer, such as aberrant methylation or LOI, may magnify the effects of genetic mutations or even have causal roles. In either case, epigenetic changes have potential value for assessing disease risk and prognosis. In a mouse model of intestinal cancer, where the adenomatous polyposis coli (Apc) gene is mutated, supplementary Igf2 LOI increases the incidence of intestinal hyperplasia. The clinical relevance of this is corroborated by the fact that patients with IGF2 LOI also have an increased risk of developing colorectal cancer [65]. Alterations involving CTCF may also be informative. Elevated CTCF expression levels have been reported in breast cancer, where it is postulated to have anti-apoptotic actions [66]. Gene activation by a CTCF homolog is observed in lung cancer [67, 68], and methylation changes in CTCF binding sites have also been reported in osteosarcoma [69]. Because epigenetic changes such as LOI and demethylation are among the earliest evens in cancer progression (reviewed in [70]), assays for epigenetic biomarkers may allow for early detection, prevention, and treatment of cancer.

4.2 IGF2 and other signaling pathways in disease pathogenesis

Igf2 overexpression sometimes occurs without apparent LOI or gene duplication. Other factors, such as sonic hedgehog (Shh), can also transcriptionally activate Igf2. Shh is a developmental morphogen involved with patterning and organ specification, and its signaling pathway is mutated in several diseases (reviewed in [71]). The Shh cascade culminates in the activation of Gli, a transcription factor that induces several target genes (Figure 4).

Figure 4
The Shh signaling pathway. A) In the absence of signal, the receptor patched (Ptc) is complexed with smoothened (Smo), and Gli exists in a truncated form that acts as a transcriptional repressor [99, 100]. B) When bound by Shh, Ptc releases Smo, which ...

Shh has been demonstrated to upregulate Igf2 both in vitro and in vivo. When mouse mesenchymal cells are treated with Shh or transfected with Gli1, Igf2 mRNA is upregulated [72]. A Ptc-deficient mutation in mice, which results in constitutive Gli activation, increases IGF2 protein levels and also the formation of medulloblastomas and rhabdomyosarcomas [73]. It is not entirely clear how Shh induces Igf2 expression. Though putative Gli-binding sites have been identified in the mouse Igf2 promoter [72], it is not known whether these sites are functional, or if they exist in the human VEGF promoter. However, functional Gli sites have been documented in the human IGFBP-6 promoter [74]. IGFBP-6 specifically binds IGF2 and is generally thought to have anti-proliferative properties. Nonetheless, like most of the IGFBPs (Table 2), IGFBP-6 can have contrasting activities, and has also been shown to be anti-apoptotic and tumorigenic (reviewed in [75]).

IGF2 itself may provide an oncogenic signal in some systems, such as the mouse mammary gland, where transgenic Igf2 overexpression induces adenocarcinomas [76]. In mouse models of rhabdomyosarcoma and medulloblastoma, Igf2 alone is insufficient to generate tumors; however, it can enhance the tumorigenic potential of Shh [73, 77]. Interestingly, tumors often overexpress the IR-A variant, which binds IGF2 with high affinity; thus, concomitant IGF2 and IR-A overexpression can potentially generate an autoproliferative loop [30]. Taken together, these observations substantiate the hypothesis that IGF2 can supply the “second hit” necessary for oncogene-induced tumors [78].

4.3 IGF2 and angiogenesis

Angiogenesis, or blood vessel growth, is another critical element of tumor progression that may involve IGF2. Oxygen, nutrients, and metabolic wastes can simply diffuse in and out of small tumors, but growth beyond a critical size (1 mm3) requires a vascular network (reviewed in [79]). Areas of hypoxia within tumors induce the expression of angiogenic factors, which prompt an influx of vessels from surrounding tissues. Neovascularization also facilitates the spread of cancer cells to other tissues; thus, there is a correlation between high metastatic potential and tumor vascularity (reviewed in [80]).

Vascular endothelial growth factor (VEGF) has a central function in both normal and pathological neovascularization, and its expression is upregulated in tumors (reviewed in [81]). Hypoxia-inducible factors (HIFs) are principle mediators of VEGF upregulation, though VEGF mRNA levels are also increased via message stabilization [82]. Transcriptional regulation also occurs through other cis elements in the VEGF promoter, and can be instigated by various growth factors, hormones, and oncogenes (reviewed in [83]).

Though studies of the IGFs in vascular development are limited, IGF2 may participate in angiogenesis through its ability to upregulate VEGF. In hepatocellular carcinomas cells, hypoxia-induced VEGF expression is increased by IGF2, which is itself upregulated by HIFs [84]. Other studies have suggested that IGF2 signaling upregulates VEGF in part by increasing HIF levels [85, 86]. Because reciprocal upregulation of IGF2 and HIF has been demonstrated [87], they may act in synergy to induce VEGF expression. Though the mechanisms remain unclear, the ability to induce VEGF accentuates the importance of IGF2 in tumor development.

IGF2 may also be involved in the pathological neovascularization that characterizes proliferative diabetic retinopathy (PDR) and retinopathy of prematurity (ROP). Several studies have implicated IGF1 in retinopathy (reviewed in [88]), but IGF2 has been largely overlooked—despite reports of 10- to 30-fold more IGF2 in the vitreous of diabetic patients than IGF1 ([89] and references therein). A recent study showed that IGFBP-3 suppressed retinal neovascularization irrespective of IGF1 levels [90], which supported the long-standing notion that IGFBPs can act independently of IGF signaling through IGF1R (reviewed in [75]). However, the potential contribution of IGF2 needs to be examined—specifically, its interactions with other receptors (such as IR-A variant) and whether these interactions are subject to IGFBP regulation. Clearly, the likely role of IGF2 in retinopathy calls for further exploration.

4.4 IGF2: the missing link between Shh and angiogenesis?

In recent years, Shh has been identified as an angiogenic factor. Studies in zebrafish reveal vascular defects in Shh-mutant embryos [91, 92], and place Shh upstream of VEGF signaling during arterial differentiation [93]. The cascades induced by Shh also appear to regulate vessel formation in mammals. In the mouse embryo, indian hedgehog (Ihh), a Shh homolog, has been suggested to be critical for early vasculogenesis [94, 95]. In Shh-deficient mice, the developing lung is poorly vascularized [96]; conversely, Shh overexpression in the neural tube results in hypervascularization [97]. Shh can also induce angiogenic factors (including VEGF) and promote neovascularization in adult mice [98]. Thus, vessel formation may depend on the ability of Shh to induce VEGF. Though the exact mechanism remains elusive, it may very well involve IGF2, which is a downstream target of the Shh cascade [72] and has a demonstrated ability to synergize with Shh [73, 77]. Moreover, IGF2 has also been shown to induce VEGF [8486]. Thus, IGF2 may mediate the angiogenic effects of Shh, and provide the critical link between Shh and VEGF.

5. Conclusions

Though interest in IGF2 has been somewhat skewed towards the study of gene regulation and imprinting, it is likely to attract attention from other fields as studies implicate IGF2 in an increasing number of diseases. The complexity of IGF2 regulation indicates that overexpression can occur at multiple levels. Since IGF2 is pivotal in many developmental and pathological processes, its multifaceted regulation presents a number of potential therapeutic targets.

Because imprinting defects are now recognized as common in the pathogenesis of cancer, the mechanisms surrounding IGF2 imprinting are likely to gain interest as well. Perhaps the most thoroughly studied of known imprinted genes, IGF2 has yielded valuable insight into other epigenetic gene regulatory mechanisms—namely X chromosome inactivation, which also gained significance with the discovery of X-linked tumor suppressors (reviewed in [37]). These studies highlight the multifactorial nature of cancer, in which IGF2 may have a pivotal role. More importantly, they suggest that imprinting and X inactivation are not just interesting epigenetic phenomena, but have considerable functional relevance.

Biographies

An external file that holds a picture, illustration, etc.
Object name is nihms45387b1.gif

Wendy Chao recently received her Ph.D. in genetics from Harvard Medical School, where her research focused on gene regulation and epigenetics. Her interests in community education have led to credits on ABC News, The Learning Channel, and in U.S. Department of Justice publications. She has been involved in science mentoring partnerships with local schools, and is on the board of advisors of the Foundation for Art and Healing in Boston, Massachusetts. Wendy is also a freelance science writer and Contributing Editor of The Scientist magazine.

An external file that holds a picture, illustration, etc.
Object name is nihms45387b2.gif

Patricia D'Amore received her Ph.D. in Biology from Boston University in 1977. She was a postdoctoral fellow at Johns Hopkins Medical School before moving to the Children's Hospital in Boston where she is currently a Research Associate in Surgery. In 1998, she became Professor of Ophthalmology (Pathology) at Harvard Medical School and a Senior Scientist at the Schepens Eye Research Institute. She is the recipient of numerous awards including the Jules & Doris Stein Research to Prevent Blindness, Senior Scientific Investigator Award, Cogan Award, and the A. Clifford Barger Excellence in Mentoring Award. She is currently the Associate Director of Research and the Ankeny Scholar of Retinal Molecular Biology at Schepens. Dr. D'Amore's research focuses on understanding the mechanism of vascular growth and development. She is the author of 112 publications.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Contributor Information

Wendy Chao, Schepens Eye Research Institute 20 Staniford Street, Boston, MA 02114, TEL: 617.912.2558, FAX: 617.912.0128, Email: wendy.chao/at/schepens.harvard.edu.

Patricia A. D’Amore, Departments of Pathology and Ophthalmology, Harvard Medical School Schepens Eye Research Institute 20 Staniford Street Boston, MA 02114, TEL: 617.912.2559, FAX: 617.912.0128. Email: patricia.damore/at/schepens.harvard.edu.

References

1. Carrel A. Artificial activiation of the growth in vitro of connective tissue. J Exp Med. 1913;17:14–9. [PMC free article] [PubMed]
2. Westwood M, Jabbour H, Bloom S, Whitehead S, Barber T, Chapman J, et al. Ten Hot Hormones. Endocrinologist. 2005 Spring;2005(75) Feature.
3. Salmon WD, Jr, Daughaday WH. A hormonally controlled serum factor which stimulates sulfate incorporation by cartilage in vitro. The Journal of laboratory and clinical medicine. 1957 Jun;49(6):825–36. [PubMed]
4. Froesch ER, Buergi H, Ramseier EB, Bally P, Labhart A. Antibody-Suppressible and Nonsuppressible Insulin-Like Activities in Human Serum and Their Physiologic Significance. an Insulin Assay with Adipose Tissue of Increased Precision and Specificity. The Journal of clinical investigation. 1963 Nov;42:1816–34. [PMC free article] [PubMed]
5. Daughaday WH, Hall K, Raben MS, Salmon WD, Jr, van den Brande JL, van Wyk JJ. Somatomedin: proposed designation for sulphation factor. Nature. 1972 Jan 14;235(5333):107. [PubMed]
6. Dulak NC, Temin HM. Multiplication-stimulating activity for chicken embryo fibroblasts from rat liver cell conditioned medium: a family of small polypeptides. Journal of cellular physiology. 1973 Apr;81(2):161–70. [PubMed]
7. Rinderknecht E, Humbel RE. Amino-terminal sequences of two polypeptides from human serum with nonsuppressible insulin-like and cell-growth-promoting activities: evidence for structural homology with insulin B chain. Proceedings of the National Academy of Sciences of the United States of America. 1976 Dec;73(12):4379–81. [PMC free article] [PubMed]
8. Marquardt H, Todaro GJ, Henderson LE, Oroszlan S. Purification and primary structure of a polypeptide with multiplication-stimulating activity from rat liver cell cultures. Homology with human insulin-like growth factor II. The Journal of biological chemistry. 1981 Jul 10;256(13):6859–65. [PubMed]
9. Daughaday WH, Hall K, Salmon WD, Jr, Van den Brande JL, Van Wyk JJ. On the nomenclature of the somatomedins and insulin-like growth factors. Endocrinology. 1987 Nov;121(5):1911–2. [PubMed]
10. Zhou Y, Xu BC, Maheshwari HG, He L, Reed M, Lozykowski M, et al. A mammalian model for Laron syndrome produced by targeted disruption of the mouse growth hormone receptor/binding protein gene (the Laron mouse) Proceedings of the National Academy of Sciences of the United States of America. 1997 Nov 25;94(24):13215–20. [PMC free article] [PubMed]
11. Denley A, Wang CC, McNeil KA, Walenkamp MJ, van Duyvenvoorde H, Wit JM, et al. Structural and functional characteristics of the Val44Met insulin-like growth factor I missense mutation: correlation with effects on growth and development. Molecular endocrinology (Baltimore, Md. 2005 Mar;19(3):711–21. [PubMed]
12. Powell-Braxton L, Hollingshead P, Warburton C, Dowd M, Pitts-Meek S, Dalton D, et al. IGF-I is required for normal embryonic growth in mice. Genes & development. 1993 Dec;7(12B):2609–17. [PubMed]
13. Baker J, Liu JP, Robertson EJ, Efstratiadis A. Role of insulin-like growth factors in embryonic and postnatal growth. Cell. 1993 Oct 8;75(1):73–82. [PubMed]
14. DeChiara TM, Robertson EJ, Efstratiadis A. Parental imprinting of the mouse insulin-like growth factor II gene. Cell. 1991 Feb 22;64(4):849–59. [PubMed]
15. LeRoith D, Roberts CT., Jr The insulin-like growth factor system and cancer. Cancer Lett. 2003 Jun 10;195(2):127–37. [PubMed]
16. Reik W, Constancia M, Dean W, Davies K, Bowden L, Murrell A, et al. Igf2 imprinting in development and disease. Int J Dev Biol. 2000;44(1):145–50. [PubMed]
17. Clemmons DR. Insulin-like growth factor binding proteins and their role in controlling IGF actions. Cytokine Growth Factor Rev. 1997 Mar;8(1):45–62. [PubMed]
18. Constancia M, Hemberger M, Hughes J, Dean W, Ferguson-Smith A, Fundele R, et al. Placental-specific IGF-II is a major modulator of placental and fetal growth. Nature. 2002 Jun 27;417(6892):945–8. [PubMed]
19. Ohlsson R, Hedborg F, Holmgren L, Walsh C, Ekstrom TJ. Overlapping patterns of IGF2 and H19 expression during human development: biallelic IGF2 expression correlates with a lack of H19 expression. Development (Cambridge, England) 1994 Feb;120(2):361–8. [PubMed]
20. de Pagter-Holthuizen P, Jansen M, van Schaik FM, van der Kammen R, Oosterwijk C, Van den Brande JL, et al. The human insulin-like growth factor II gene contains two development-specific promoters. FEBS letters. 1987 Apr 20;214(2):259–64. [PubMed]
21. Rotwein P, Hall LJ. Evolution of insulin-like growth factor II: characterization of the mouse IGF-II gene and identification of two pseudo-exons. DNA and cell biology. 1990 Dec;9(10):725–35. [PubMed]
22. Lewis A, Reik W. How imprinting centres work. Cytogenet Genome Res. 2006;113(1–4):81–9. [PubMed]
23. Thorvaldsen JL, Duran KL, Bartolomei MS. Deletion of the H19 differentially methylated domain results in loss of imprinted expression of H19 and Igf2. Genes & development. 1998 Dec 1;12(23):3693–702. [PMC free article] [PubMed]
24. Ohlsson R, Renkawitz R, Lobanenkov V. CTCF is a uniquely versatile transcription regulator linked to epigenetics and disease. Trends Genet. 2001 Sep;17(9):520–7. [PubMed]
25. Bell AC, Felsenfeld G. Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene. Nature. 2000 May 25;405(6785):482–5. [PubMed]
26. Chao W, Huynh KD, Spencer RJ, Davidow LS, Lee JT. CTCF, a candidate transacting factor for X-inactivation choice. Science (New York, NY. 2002 Jan 11;295(5553):345–7. [PubMed]
27. Boumil RM, Ogawa Y, Sun BK, Huynh KD, Lee JT. Differential methylation of Xite and CTCF sites in Tsix mirrors the pattern of X-inactivation choice in mice. Molecular and cellular biology. 2006 Mar;26(6):2109–17. [PMC free article] [PubMed]
28. Stavropoulos N, Rowntree RK, Lee JT. Identification of developmentally specific enhancers for Tsix in the regulation of X chromosome inactivation. Molecular and cellular biology. 2005 Apr;25(7):2757–69. [PMC free article] [PubMed]
29. Lyon MF. Gene action in the X-chromosome of the mouse (Mus musculus L.) Nature. 1961 Apr 22;190:372–3. [PubMed]
30. Thorvaldsen JL, Verona RI, Bartolomei MS. X-tra! X-tra! News from the mouse X chromosome. Developmental biology. 2006 Oct 15;298(2):344–53. [PubMed]
31. Lee JT, Davidow LS, Warshawsky D. Tsix, a gene antisense to Xist at the X-inactivation centre. Nature genetics. 1999 Apr;21(4):400–4. [PubMed]
32. Kim TH, Abdullaev ZK, Smith AD, Ching KA, Loukinov DI, Green RD, et al. Analysis of the vertebrate insulator protein CTCF-binding sites in the human genome. Cell. 2007 Mar 23;128(6):1231–45. [PMC free article] [PubMed]
33. Do Kim J, Hinz AK, Ha Choo J, Stubbs L, Kim J. YY1 as a controlling factor for the Peg3 and Gnas imprinted domains. Genomics. 2007 Feb;89(2):262–9. [PMC free article] [PubMed]
34. Donohoe ME, Zhang LF, Xu N, Shi Y, Lee JT. Identification of a Ctcf cofactor, Yy1, for the X chromosome binary switch. Mol Cell. 2007 Jan 12;25(1):43–56. [PubMed]
35. Ling JQ, Li T, Hu JF, Vu TH, Chen HL, Qiu XW, et al. CTCF mediates interchromosomal colocalization between Igf2/H19 and Wsb1/Nf1. Science (New York, NY. 2006 Apr 14;312(5771):269–72. [PubMed]
36. Lupski JR, Stankiewicz P. Genomic disorders: molecular mechanisms for rearrangements and conveyed phenotypes. PLoS genetics. 2005 Dec;1(6):e49. [PMC free article] [PubMed]
37. Medema RH, Burgering BM. The X Factor: Skewing X Inactivation towards Cancer. Cell. 2007 Jun 29;129(7):1253–4. [PubMed]
38. Zuo T, Wang L, Morrison C, Chang X, Zhang H, Li W, et al. FOXP3 Is an X-Linked Breast Cancer Suppressor Gene and an Important Repressor of the HER-2/ErbB2 Oncogene. Cell. 2007 Jun 29;129(7):1275–86. [PMC free article] [PubMed]
39. Foulstone E, Prince S, Zaccheo O, Burns JL, Harper J, Jacobs C, et al. Insulin-like growth factor ligands, receptors, and binding proteins in cancer. The Journal of pathology. 2005 Jan;205(2):145–53. [PubMed]
40. Rivera MN, Kim WJ, Wells J, Driscoll DR, Brannigan BW, Han M, et al. An X chromosome gene, WTX, is commonly inactivated in Wilms tumor. Science (New York, NY. 2007 Feb 2;315(5812):642–5. [PubMed]
41. Moore T, Constancia M, Zubair M, Bailleul B, Feil R, Sasaki H, et al. Multiple imprinted sense and antisense transcripts, differential methylation and tandem repeats in a putative imprinting control region upstream of mouse Igf2. Proceedings of the National Academy of Sciences of the United States of America. 1997 Nov 11;94(23):12509–14. [PMC free article] [PubMed]
42. Okutsu T, Kuroiwa Y, Kagitani F, Kai M, Aisaka K, Tsutsumi O, et al. Expression and imprinting status of human PEG8/IGF2AS, a paternally expressed antisense transcript from the IGF2 locus, in Wilms' tumors. J Biochem (Tokyo) 2000 Mar;127(3):475–83. [PubMed]
43. Vu TH, Chuyen NV, Li T, Hoffman AR. Loss of imprinting of IGF2 sense and antisense transcripts in Wilms' tumor. Cancer research. 2003 Apr 15;63(8):1900–5. [PubMed]
44. Denley A, Wallace JC, Cosgrove LJ, Forbes BE. The insulin receptor isoform exon 11- (IR-A) in cancer and other diseases: a review. Hormone and metabolic research Hormon- und Stoffwechselforschung. 2003 Nov–Dec;35(11–12):778–85. [PubMed]
45. Denley A, Bonython ER, Booker GW, Cosgrove LJ, Forbes BE, Ward CW, et al. Structural determinants for high-affinity binding of insulin-like growth factor II to insulin receptor (IR)-A, the exon 11 minus isoform of the IR. Molecular endocrinology (Baltimore, Md. 2004 Oct;18(10):2502–12. [PubMed]
46. White MF. Regulating insulin signaling and beta-cell function through IRS proteins. Canadian journal of physiology and pharmacology. 2006 Jul;84(7):725–37. [PubMed]
47. Denley A, Cosgrove LJ, Booker GW, Wallace JC, Forbes BE. Molecular interactions of the IGF system. Cytokine Growth Factor Rev. 2005 Aug–Oct;16(4–5):421–39. [PubMed]
48. Scott CD, Firth SM. The role of the M6P/IGF-II receptor in cancer: tumor suppression or garbage disposal? Hormone and metabolic research Hormon- und Stoffwechselforschung. 2004 May;36(5):261–71. [PubMed]
49. Petley T, Graff K, Jiang W, Yang H, Florini J. Variation among cell types in the signaling pathways by which IGF-I stimulates specific cellular responses. Hormone and metabolic research Hormon- und Stoffwechselforschung. 1999 Feb–Mar;31(2–3):70–6. [PubMed]
50. Baserga R, Peruzzi F, Reiss K. The IGF-1 receptor in cancer biology. Int J Cancer. 2003 Dec 20;107(6):873–7. [PubMed]
51. Hennessy BT, Smith DL, Ram PT, Lu Y, Mills GB. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov. 2005 Dec;4(12):988–1004. [PubMed]
52. Wilson EM, Hsieh MM, Rotwein P. Autocrine growth factor signaling by insulin-like growth factor-II mediates MyoD-stimulated myocyte maturation. The Journal of biological chemistry. 2003 Oct 17;278(42):41109–13. [PubMed]
53. Wilson EM, Rotwein P. Control of MyoD function during initiation of muscle differentiation by an autocrine signaling pathway activated by insulin-like growth factor-II. The Journal of biological chemistry. 2006 Oct 6;281(40):29962–71. [PubMed]
54. Minuto F, Palermo C, Arvigo M, Barreca AM. The IGF system and bone. J Endocrinol Invest. 2005;28(8 Suppl):8–10. [PubMed]
55. Wang ZQ, Fung MR, Barlow DP, Wagner EF. Regulation of embryonic growth and lysosomal targeting by the imprinted Igf2/Mpr gene. Nature. 1994 Dec 1;372(6505):464–7. [PubMed]
56. Leighton PA, Ingram RS, Eggenschwiler J, Efstratiadis A, Tilghman SM. Disruption of imprinting caused by deletion of the H19 gene region in mice. Nature. 1995 May 4;375(6526):34–9. [PubMed]
57. Sun FL, Dean WL, Kelsey G, Allen ND, Reik W. Transactivation of Igf2 in a mouse model of Beckwith-Wiedemann syndrome. Nature. 1997 Oct 23;389(6653):809–15. [PubMed]
58. Morison IM, Reeve AE. Insulin-like growth factor 2 and overgrowth: molecular biology and clinical implications. Mol Med Today. 1998 Mar;4(3):110–5. [PubMed]
59. Sparago A, Cerrato F, Vernucci M, Ferrero GB, Silengo MC, Riccio A. Microdeletions in the human H19 DMR result in loss of IGF2 imprinting and Beckwith-Wiedemann syndrome. Nature genetics. 2004 Sep;36(9):958–60. [PubMed]
60. Prawitt D, Enklaar T, Gartner-Rupprecht B, Spangenberg C, Oswald M, Lausch E, et al. Microdeletion of target sites for insulator protein CTCF in a chromosome 11p15 imprinting center in Beckwith-Wiedemann syndrome and Wilms' tumor. Proceedings of the National Academy of Sciences of the United States of America. 2005 Mar 15;102(11):4085–90. [PMC free article] [PubMed]
61. Feinberg AP, Ohlsson R, Henikoff S. The epigenetic progenitor origin of human cancer. Nature reviews. 2006 Jan;7(1):21–33. [PubMed]
62. Bae SK, Bae MH, Ahn MY, Son MJ, Lee YM, Bae MK, et al. Egr-1 mediates transcriptional activation of IGF-II gene in response to hypoxia. Cancer research. 1999 Dec 1;59(23):5989–94. [PubMed]
63. Ravenel JD, Broman KW, Perlman EJ, Niemitz EL, Jayawardena TM, Bell DW, et al. Loss of imprinting of insulin-like growth factor-II (IGF2) gene in distinguishing specific biologic subtypes of Wilms tumor. J Natl Cancer Inst. 2001 Nov 21;93(22):1698–703. [PubMed]
64. McCann AH, Miller N, O'Meara A, Pedersen I, Keogh K, Gorey T, et al. Biallelic expression of the IGF2 gene in human breast disease. Human molecular genetics. 1996 Aug;5(8):1123–7. [PubMed]
65. Kaneda A, Feinberg AP. Loss of imprinting of IGF2: a common epigenetic modifier of intestinal tumor risk. Cancer research. 2005 Dec 15;65(24):11236–40. [PubMed]
66. Docquier F, Farrar D, D'Arcy V, Chernukhin I, Robinson AF, Loukinov D, et al. Heightened expression of CTCF in breast cancer cells is associated with resistance to apoptosis. Cancer research. 2005 Jun 15;65(12):5112–22. [PubMed]
67. Hong JA, Kang Y, Abdullaev Z, Flanagan PT, Pack SD, Fischette MR, et al. Reciprocal binding of CTCF and BORIS to the NY-ESO-1 promoter coincides with derepression of this cancer-testis gene in lung cancer cells. Cancer research. 2005 Sep 1;65(17):7763–74. [PubMed]
68. Vatolin S, Abdullaev Z, Pack SD, Flanagan PT, Custer M, Loukinov DI, et al. Conditional expression of the CTCF-paralogous transcriptional factor BORIS in normal cells results in demethylation and derepression of MAGE-A1 and reactivation of other cancer-testis genes. Cancer research. 2005 Sep 1;65(17):7751–62. [PubMed]
69. Ulaner GA, Vu TH, Li T, Hu JF, Yao XM, Yang Y, et al. Loss of imprinting of IGF2 and H19 in osteosarcoma is accompanied by reciprocal methylation changes of a CTCF-binding site. Human molecular genetics. 2003 Mar 1;12(5):535–49. [PubMed]
70. Jelinic P, Shaw P. Loss of imprinting and cancer. The Journal of pathology. 2007 Feb;211(3):261–8. [PubMed]
71. Ruiz i Altaba A, Sanchez P, Dahmane N. Gli and hedgehog in cancer: tumours, embryos and stem cells. Nat Rev Cancer. 2002 May;2(5):361–72. [PubMed]
72. Ingram WJ, Wicking CA, Grimmond SM, Forrest AR, Wainwright BJ. Novel genes regulated by Sonic Hedgehog in pluripotent mesenchymal cells. Oncogene. 2002 Nov 21;21(53):8196–205. [PubMed]
73. Hahn H, Wojnowski L, Specht K, Kappler R, Calzada-Wack J, Potter D, et al. Patched target Igf2 is indispensable for the formation of medulloblastoma and rhabdomyosarcoma. The Journal of biological chemistry. 2000 Sep 15;275(37):28341–4. [PubMed]
74. Yoon JW, Kita Y, Frank DJ, Majewski RR, Konicek BA, Nobrega MA, et al. Gene expression profiling leads to identification of GLI1-binding elements in target genes and a role for multiple downstream pathways in GLI1-induced cell transformation. The Journal of biological chemistry. 2002 Feb 15;277(7):5548–55. [PubMed]
75. Firth SM, Baxter RC. Cellular actions of the insulin-like growth factor binding proteins. Endocr Rev. 2002 Dec;23(6):824–54. [PubMed]
76. Bates P, Fisher R, Ward A, Richardson L, Hill DJ, Graham CF. Mammary cancer in transgenic mice expressing insulin-like growth factor II (IGF-II) Br J Cancer. 1995 Nov;72(5):1189–93. [PMC free article] [PubMed]
77. Rao G, Pedone CA, Valle LD, Reiss K, Holland EC, Fults DW. Sonic hedgehog and insulin-like growth factor signaling synergize to induce medulloblastoma formation from nestin-expressing neural progenitors in mice. Oncogene. 2004 Aug 12;23(36):6156–62. [PubMed]
78. Christofori G, Naik P, Hanahan D. A second signal supplied by insulin-like growth factor II in oncogene-induced tumorigenesis. Nature. 1994 Jun 2;369(6479):414–8. [PubMed]
79. Sivridis E, Giatromanolaki A, Koukourakis MI. The vascular network of tumours--what is it not for? The Journal of pathology. 2003 Oct;201(2):173–80. [PubMed]
80. Semenza GL. Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Biol. 1999;15:551–78. [PubMed]
81. Dvorak HF. Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol. 2002 Nov 1;20(21):4368–80. [PubMed]
82. Shima DT, Deutsch U, D'Amore PA. Hypoxic induction of vascular endothelial growth factor (VEGF) in human epithelial cells is mediated by increases in mRNA stability. FEBS letters. 1995 Aug 21;370(3):203–8. [PubMed]
83. Loureiro RM, D'Amore PA. Transcriptional regulation of vascular endothelial growth factor in cancer. Cytokine Growth Factor Rev. 2005 Feb;16(1):77–89. [PubMed]
84. Kim KW, Bae SK, Lee OH, Bae MH, Lee MJ, Park BC. Insulin-like growth factor II induced by hypoxia may contribute to angiogenesis of human hepatocellular carcinoma. Cancer research. 1998 Jan 15;58(2):348–51. [PubMed]
85. Kwon YW, Kwon KS, Moon HE, Park JA, Choi KS, Kim YS, et al. Insulin-like growth factor-II regulates the expression of vascular endothelial growth factor by the human keratinocyte cell line HaCaT. J Invest Dermatol. 2004 Jul;123(1):152–8. [PubMed]
86. Kim HJ, Kim TY. Regulation of vascular endothelial growth factor expression by insulin-like growth factor-II in human keratinocytes, differential involvement of mitogen-activated protein kinases and feedback inhibition of protein kinase C. Br J Dermatol. 2005 Mar;152(3):418–25. [PubMed]
87. Feldser D, Agani F, Iyer NV, Pak B, Ferreira G, Semenza GL. Reciprocal positive regulation of hypoxia-inducible factor 1alpha and insulin-like growth factor 2. Cancer research. 1999 Aug 15;59(16):3915–8. [PubMed]
88. Chen J, Smith LE. Retinopathy of prematurity. Angiogenesis. 2007;10(2):133–40. [PubMed]
89. Guidry C, Feist R, Morris R, Hardwick CW. Changes in IGF activities in human diabetic vitreous. Diabetes. 2004 Sep;53(9):2428–35. [PubMed]
90. Lofqvist C, Chen J, Connor KM, Smith AC, Aderman CM, Liu N, et al. From the Cover: IGFBP3 suppresses retinopathy through suppression of oxygen-induced vessel loss and promotion of vascular regrowth. Proceedings of the National Academy of Sciences of the United States of America. 2007 Jun 19;104(25):10589–94. [PMC free article] [PubMed]
91. Chen JN, Haffter P, Odenthal J, Vogelsang E, Brand M, van Eeden FJ, et al. Mutations affecting the cardiovascular system and other internal organs in zebrafish. Development (Cambridge, England) 1996 Dec;123:293–302. [PubMed]
92. Brown LA, Rodaway AR, Schilling TF, Jowett T, Ingham PW, Patient RK, et al. Insights into early vasculogenesis revealed by expression of the ETS-domain transcription factor Fli-1 in wild-type and mutant zebrafish embryos. Mech Dev. 2000 Feb;90(2):237–52. [PubMed]
93. Lawson ND, Vogel AM, Weinstein BM. sonic hedgehog and vascular endothelial growth factor act upstream of the Notch pathway during arterial endothelial differentiation. Dev Cell. 2002 Jul;3(1):127–36. [PubMed]
94. Dyer MA, Farrington SM, Mohn D, Munday JR, Baron MH. Indian hedgehog activates hematopoiesis and vasculogenesis and can respecify prospective neurectodermal cell fate in the mouse embryo. Development (Cambridge, England) 2001 May;128(10):1717–30. [PubMed]
95. Byrd N, Becker S, Maye P, Narasimhaiah R, St-Jacques B, Zhang X, et al. Hedgehog is required for murine yolk sac angiogenesis. Development (Cambridge, England) 2002 Jan;129(2):361–72. [PubMed]
96. Pepicelli CV, Lewis PM, McMahon AP. Sonic hedgehog regulates branching morphogenesis in the mammalian lung. Curr Biol. 1998 Sep 24;8(19):1083–6. [PubMed]
97. Rowitch DHBSJ, Lee SM, Flax JD, Snyder EY, McMahon AP. Sonic hedgehog regulates proliferation and inhibits differentiation of CNS precursor cells. J Neurosci. 1999 Oct 15;19(20):8954–65. [PubMed]
98. Pola R, Ling LE, Silver M, Corbley MJ, Kearney M, Blake Pepinsky R, et al. The morphogen Sonic hedgehog is an indirect angiogenic agent upregulating two families of angiogenic growth factors. Nature medicine. 2001 Jun;7(6):706–11. [PubMed]
99. Ruiz i Altaba A. Gli proteins encode context-dependent positive and negative functions: implications for development and disease. Development (Cambridge, England) 1999 Jun;126(14):3205–16. [PubMed]
100. Sasaki H, Nishizaki Y, Hui C, Nakafuku M, Kondoh H. Regulation of Gli2 and Gli3 activities by an amino-terminal repression domain: implication of Gli2 and Gli3 as primary mediators of Shh signaling. Development (Cambridge, England) 1999 Sep;126(17):3915–24. [PubMed]

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...