Dwarfism and Impaired Gut Development in Insulin-Like Growth Factor II mRNA-Binding Protein 1-Deficient Mice

Abstract

Insulin-like growth factor II mRNA-binding protein 1 (IMP1) belongs to a family of RNA-binding proteins implicated in mRNA localization, turnover, and translational control. Mouse IMP1 is expressed during early development, and an increase in expression occurs around embryonic day 12.5 (E12.5). To characterize the physiological role of IMP1, we generated IMP1-deficient mice carrying a gene trap insertion in the Imp1 gene. Imp1؊/؊ mice were on average 40% smaller than wild-type and heterozygous sex-matched littermates. Growth retardation was apparent from E17.5 and remained permanent into adult life. Moreover, Imp1؊/؊ mice exhibited high perinatal mortality, and only 50% were alive 3 days after birth. In contrast to most other organs, intestinal epithelial cells continue to express IMP1 postnatally, and Imp1 ؊/؊ mice exhibited impaired development of the intestine, with small and misshapen villi and twisted colon crypts. Analysis of target mRNAs and global expression profiling at E12.5 indicated that Igf2 translation was downregulated, whereas the postnatal intestine showed reduced expression of transcripts encoding extracellular matrix components, such as galectin-1, lumican, tenascin-C, procollagen transcripts, and the Hsp47 procollagen chaperone. Taken together, the results demonstrate that IMP1 is essential for normal growth and development. Moreover, IMP1 may facilitate intestinal morphogenesis via regulation of extracellular matrix formation.Insulin-like growth factor II (IGF-II) mRNA-binding protein 1 (IMP1) and the closely related IMP2 and IMP3 proteins belong to a conserved family of RNA-binding proteins consisting of two RNA recognition motifs (RRM) and four K-homology (KH) domains (for review, see references 36 and 56). The latter are phylogenetically conserved in Drosophila melanogaster and Caenorhabditis elegans (GenBank T23837) and constitute a functionally independent entity (37). IMP1 is orthologous to the chicken zipcode-binding protein 1 (ZBP1) and the mouse c-Myc coding region determinant-binding protein (CRD-BP) (10, 45), whereas IMP3 is orthologous to the Xenopus laevis Vg1 mRNA-binding protein (Vg1-RBP/Vera) (8, 16). IMP2 has diverged phylogenetically from IMP1 and IMP3 and has no known orthologues, but a splice variant p62 has been isolated from hepatic carcinoma (59).So far only a handful of mRNAs, including Igf2 leader 3, H19, c-myc, ␤-actin, and Vg1 mRNAs, have been identified as targets for the proteins (16,25,39,45,48). Binding sites are located in the 5Ј untranslated region (UTR), the coding region, and the 3Ј UTR of the mRNAs. Similar to other RNA-binding proteins such as Bruno, which mediates translational repression of oskar mRNA in D. melanogaster (24), multiple IMP molecules may associate with the RNA target. So far, there is no absolute consensus about the nature of the IMP attachment site. Therefore, it is not possible to predict putative target mRNAs solely on the basis of their sequences.The IMPs have been implicated in posttranscriptional processes such as mRNA localization,...

Expression of the RNA-binding protein IMP1 correlates with poor prognosis in ovarian carcinoma

“…In agreement with a recent study suggesting aberrant IMP expression in ovarian carcinomas on the basis of semiquantitative RT-PCR analyses (Gu et al, 2004), the majority of here analysed ovarian carcinoma samples (69% of cases) expressed IMP1 without any stromal background. Normal surface epithelium of the ovary was negative for IMP1 supporting the finding that IMP1 is almost exclusively expressed during embryogenesis, (Mueller-Pillasch et al, 1999;Nielsen et al, 1999;Hansen et al, 2004). Notably, IMP1 expression was not detected in borderline tumors of the ovary providing further evidence that SBOTs are not precursors of high-grade serous carcinomas (Shih Ie and Kurman, 2004).…”

“…Members of the protein family direct mRNA localization, translation or mRNA stability of their target transcripts (Yisraeli, 2005). All IMP proteins are primarily expressed during embryogenesis and mid-gestation in mouse with almost no detectable expression in the postnatal phase (Mueller-Pillasch et al, 1999;Nielsen et al, 1999;Hansen et al, 2004). Deletion of IMP1 expression in mice results in dwarfism, impaired development of the gut and increased perinatal lethality (Hansen et al, 2004).…”

“…All IMP proteins are primarily expressed during embryogenesis and mid-gestation in mouse with almost no detectable expression in the postnatal phase (Mueller-Pillasch et al, 1999;Nielsen et al, 1999;Hansen et al, 2004). Deletion of IMP1 expression in mice results in dwarfism, impaired development of the gut and increased perinatal lethality (Hansen et al, 2004). In Xenopus, the ortholog Vg1-RBP is essential for the control of neuronal crest cell migration (Yaniv et al, 2003).…”

Targeted Knockdown of the RNA-binding Protein CRD-BP Promotes Cell Proliferation via an Insulin-like Growth Factor II-dependent Pathway in Human K562 Leukemia Cells

“…Accordingly, CRD-BP may normally inhibit human K562 leukemia cell proliferation. This was unexpected based upon its suspected role as an oncoprotein and recent observations that CRD-BP-deficient mice are dwarfs and that their cultured embryo fibroblasts exhibit reduced proliferation rates (20). Therefore, CRD-BP may regulate cell proliferation in a cell typespecific manner.…”

Differential regulation of the insulin‐like growth factor II mRNA‐binding protein genes by architectural transcription factor HMGA2

“…Because of the drastic downregulation of IMP2 in the HMGA2 knockout models, we could predict a similar growth retarded phenotype for the IMP2 À=À mouse, pointing to a very important role of the HMGA2-IMP2 pathway in embryonic development. In this regard, it is interesting to note that the recently published Imp1-deficient mice were on an average 40% smaller than wildtype and heterozygous sex-matched littermates [32].…”