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Glypican-3-deficient mice exhibit developmental overgrowth and some of the abnormalities typical of Simpson-Golabi-Behmel syndrome.

Cano-Gauci DF, Song HH, Yang H, McKerlie C, Choo B, Shi W, Pullano R, Piscione TD, Grisaru S, Soon S, Sedlackova L, Tanswell AK, Mak TW, Yeger H, Lockwood GA, Rosenblum ND, Filmus J - J. Cell Biol. (1999)

Bottom Line: These patients display pre- and postnatal overgrowth, and a varying range of dysmorphisms.Since BWS has been associated with biallelic expression of insulin-like growth factor II (IGF-II), it has been proposed that GPC3 is a negative regulator of IGF-II.In the particular case of the kidney, we demonstrate that there is an early and persistent developmental abnormality of the ureteric bud/collecting system due to increased proliferation of cells in this tissue element.

View Article: PubMed Central - PubMed

Affiliation: The Ontario Cancer Institute, Toronto, Ontario, M5G 2M9 Canada.

ABSTRACT
Glypicans are a family of heparan sulfate proteoglycans that are linked to the cell surface through a glycosyl-phosphatidylinositol anchor. One member of this family, glypican-3 (Gpc3), is mutated in patients with the Simpson-Golabi-Behmel syndrome (SGBS). These patients display pre- and postnatal overgrowth, and a varying range of dysmorphisms. The clinical features of SGBS are very similar to the more extensively studied Beckwith-Wiedemann syndrome (BWS). Since BWS has been associated with biallelic expression of insulin-like growth factor II (IGF-II), it has been proposed that GPC3 is a negative regulator of IGF-II. However, there is still no biochemical evidence indicating that GPC3 plays such a role.Here, we report that GPC3-deficient mice exhibit several of the clinical features observed in SGBS patients, including developmental overgrowth, perinatal death, cystic and dyplastic kidneys, and abnormal lung development. A proportion of the mutant mice also display mandibular hypoplasia and an imperforate vagina. In the particular case of the kidney, we demonstrate that there is an early and persistent developmental abnormality of the ureteric bud/collecting system due to increased proliferation of cells in this tissue element. The degree of developmental overgrowth of the GPC3-deficient mice is similar to that of mice deficient in IGF receptor type 2 (IGF2R), a well characterized negative regulator of IGF-II. Unlike the IGF2R-deficient mice, however, the levels of IGF-II in GPC3 knockouts are similar to those of the normal littermates.

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Comparative analysis of IGF-II levels in serum, whole embryo, lung, liver, and kidney. (A) Circulating levels of IGF-II at different time points during development. (B) Levels of IGF-II in whole embryos at E12.5 and E14.5. Each bar represents the mean + SEM obtained by densitometric scanning of four pooled samples done in duplicate. Inset shows a representative image of the Western blot. (C) IGF-II mRNA levels were measured by Northern blot analysis and normalized with the intensity of the corresponding GAPDH band. Each bar represents the mean + SEM obtained by densitometric scanning of two different samples.
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Figure 6: Comparative analysis of IGF-II levels in serum, whole embryo, lung, liver, and kidney. (A) Circulating levels of IGF-II at different time points during development. (B) Levels of IGF-II in whole embryos at E12.5 and E14.5. Each bar represents the mean + SEM obtained by densitometric scanning of four pooled samples done in duplicate. Inset shows a representative image of the Western blot. (C) IGF-II mRNA levels were measured by Northern blot analysis and normalized with the intensity of the corresponding GAPDH band. Each bar represents the mean + SEM obtained by densitometric scanning of two different samples.

Mentions: Currently, the molecular basis by which GPC3 regulates growth is unknown. Based on the phenotypic overlap between SGBS and BWS, and the fact that biallelic expression of IGF-II has been associated with BWS, it has been proposed that GPC3 is a negative regulator of IGF-II (Pilia et al. 1996). Interestingly, developmental overgrowth of a similar magnitude to that observed in GPC3-deficient mice has been reported in IGF2R-deficient mice (Lau et al. 1994; Wang et al. 1994). These mice have increased levels of circulating (about fourfold) and tissue (about twofold) IGF-II (Lau et al. 1994). This is not surprising, since this receptor binds IGF-II and downregulates its activity by endocytosis and degradation. Thus, to investigate whether the overgrowth observed in the GPC3-deficient mice could also be due to increased levels of IGF-II, we measured its serum and tissue levels in wild-type and Gpc3-mutant mice. As shown in Fig. 6 A, the mutant mice show no significant differences in circulating IGF-II levels compared with wild-type at developmental stages in which overgrowth in the GPC3-deficient mice was documented. We also compared the levels of IGF-II in protein extracts of whole embryos at E12.5 and E14.5. As shown in Fig. 6, IGF-II levels were similar in Gpc3 −/ embryos and their normal littermates. Since the levels of mature IGF-II in embryonic liver, lung, and kidney are too low to be measured accurately by Western blot, we assessed the levels of IGF-II mRNA in liver, lung, and kidney of E18 embryos by Northern blot. No significant difference could be detected between Gpc3 −/ and normal littermates (Fig. 6).


Glypican-3-deficient mice exhibit developmental overgrowth and some of the abnormalities typical of Simpson-Golabi-Behmel syndrome.

Cano-Gauci DF, Song HH, Yang H, McKerlie C, Choo B, Shi W, Pullano R, Piscione TD, Grisaru S, Soon S, Sedlackova L, Tanswell AK, Mak TW, Yeger H, Lockwood GA, Rosenblum ND, Filmus J - J. Cell Biol. (1999)

Comparative analysis of IGF-II levels in serum, whole embryo, lung, liver, and kidney. (A) Circulating levels of IGF-II at different time points during development. (B) Levels of IGF-II in whole embryos at E12.5 and E14.5. Each bar represents the mean + SEM obtained by densitometric scanning of four pooled samples done in duplicate. Inset shows a representative image of the Western blot. (C) IGF-II mRNA levels were measured by Northern blot analysis and normalized with the intensity of the corresponding GAPDH band. Each bar represents the mean + SEM obtained by densitometric scanning of two different samples.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199732&req=5

Figure 6: Comparative analysis of IGF-II levels in serum, whole embryo, lung, liver, and kidney. (A) Circulating levels of IGF-II at different time points during development. (B) Levels of IGF-II in whole embryos at E12.5 and E14.5. Each bar represents the mean + SEM obtained by densitometric scanning of four pooled samples done in duplicate. Inset shows a representative image of the Western blot. (C) IGF-II mRNA levels were measured by Northern blot analysis and normalized with the intensity of the corresponding GAPDH band. Each bar represents the mean + SEM obtained by densitometric scanning of two different samples.
Mentions: Currently, the molecular basis by which GPC3 regulates growth is unknown. Based on the phenotypic overlap between SGBS and BWS, and the fact that biallelic expression of IGF-II has been associated with BWS, it has been proposed that GPC3 is a negative regulator of IGF-II (Pilia et al. 1996). Interestingly, developmental overgrowth of a similar magnitude to that observed in GPC3-deficient mice has been reported in IGF2R-deficient mice (Lau et al. 1994; Wang et al. 1994). These mice have increased levels of circulating (about fourfold) and tissue (about twofold) IGF-II (Lau et al. 1994). This is not surprising, since this receptor binds IGF-II and downregulates its activity by endocytosis and degradation. Thus, to investigate whether the overgrowth observed in the GPC3-deficient mice could also be due to increased levels of IGF-II, we measured its serum and tissue levels in wild-type and Gpc3-mutant mice. As shown in Fig. 6 A, the mutant mice show no significant differences in circulating IGF-II levels compared with wild-type at developmental stages in which overgrowth in the GPC3-deficient mice was documented. We also compared the levels of IGF-II in protein extracts of whole embryos at E12.5 and E14.5. As shown in Fig. 6, IGF-II levels were similar in Gpc3 −/ embryos and their normal littermates. Since the levels of mature IGF-II in embryonic liver, lung, and kidney are too low to be measured accurately by Western blot, we assessed the levels of IGF-II mRNA in liver, lung, and kidney of E18 embryos by Northern blot. No significant difference could be detected between Gpc3 −/ and normal littermates (Fig. 6).

Bottom Line: These patients display pre- and postnatal overgrowth, and a varying range of dysmorphisms.Since BWS has been associated with biallelic expression of insulin-like growth factor II (IGF-II), it has been proposed that GPC3 is a negative regulator of IGF-II.In the particular case of the kidney, we demonstrate that there is an early and persistent developmental abnormality of the ureteric bud/collecting system due to increased proliferation of cells in this tissue element.

View Article: PubMed Central - PubMed

Affiliation: The Ontario Cancer Institute, Toronto, Ontario, M5G 2M9 Canada.

ABSTRACT
Glypicans are a family of heparan sulfate proteoglycans that are linked to the cell surface through a glycosyl-phosphatidylinositol anchor. One member of this family, glypican-3 (Gpc3), is mutated in patients with the Simpson-Golabi-Behmel syndrome (SGBS). These patients display pre- and postnatal overgrowth, and a varying range of dysmorphisms. The clinical features of SGBS are very similar to the more extensively studied Beckwith-Wiedemann syndrome (BWS). Since BWS has been associated with biallelic expression of insulin-like growth factor II (IGF-II), it has been proposed that GPC3 is a negative regulator of IGF-II. However, there is still no biochemical evidence indicating that GPC3 plays such a role.Here, we report that GPC3-deficient mice exhibit several of the clinical features observed in SGBS patients, including developmental overgrowth, perinatal death, cystic and dyplastic kidneys, and abnormal lung development. A proportion of the mutant mice also display mandibular hypoplasia and an imperforate vagina. In the particular case of the kidney, we demonstrate that there is an early and persistent developmental abnormality of the ureteric bud/collecting system due to increased proliferation of cells in this tissue element. The degree of developmental overgrowth of the GPC3-deficient mice is similar to that of mice deficient in IGF receptor type 2 (IGF2R), a well characterized negative regulator of IGF-II. Unlike the IGF2R-deficient mice, however, the levels of IGF-II in GPC3 knockouts are similar to those of the normal littermates.

Show MeSH
Related in: MedlinePlus