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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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Kidney development in the Gpc3 −/ mouse. Paraffin-embedded tissue sections were generated from fixed tissue isolated from +/+ and −/ mice. E12.0 sections were imaged at 200×. Bar, 37.5 μm. E13.5, E16.5, and E18.5 sections were imaged at 100×. Bar, 75 μm. At E12.0, branching of the ureteric bud is markedly enhanced in the −/ versus +/+ embryo (arrowheads). By E13.5, the −/ kidney is much larger than that of its +/+ littermate and consists of histologically normal ureteric bud and mesenchymal-derived tissue elements. While these mesenchymal-derived elements (glomeruli and tubules) are present in the cortex (C) of the E16.5 −/ and +/+ kidneys, they are disorganized in the −/ cortex and the −/ medulla (M) is relatively devoid of tubular structures. Cysts (Cy) are present in −/ medulla in an irregular pattern. At E18.5, these abnormalities persist in the −/ kidney and are accompanied by total absence of the medullary tubular patterning characteristic of the +/+ kidney.
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Figure 7: Kidney development in the Gpc3 −/ mouse. Paraffin-embedded tissue sections were generated from fixed tissue isolated from +/+ and −/ mice. E12.0 sections were imaged at 200×. Bar, 37.5 μm. E13.5, E16.5, and E18.5 sections were imaged at 100×. Bar, 75 μm. At E12.0, branching of the ureteric bud is markedly enhanced in the −/ versus +/+ embryo (arrowheads). By E13.5, the −/ kidney is much larger than that of its +/+ littermate and consists of histologically normal ureteric bud and mesenchymal-derived tissue elements. While these mesenchymal-derived elements (glomeruli and tubules) are present in the cortex (C) of the E16.5 −/ and +/+ kidneys, they are disorganized in the −/ cortex and the −/ medulla (M) is relatively devoid of tubular structures. Cysts (Cy) are present in −/ medulla in an irregular pattern. At E18.5, these abnormalities persist in the −/ kidney and are accompanied by total absence of the medullary tubular patterning characteristic of the +/+ kidney.

Mentions: To determine if GPC3-deficient mice exhibit overgrowth, as SGBS patients do, we compared the weight of Gpc3 −/, +/−, and +/+ littermates at different stages of embryonic development. Fig. 5 shows that the Gpc3 −/ mice were significantly heavier than the wild-type littermates at every time point analyzed. The overgrowth was greater at the time of birth, when the GPC3-deficient mice were ∼30% heavier than normal littermates. Heterozygotes displayed an intermediate size at all time points. When we compared heart, lung, and liver weight as percentage of body weight at different embryonic stages, we found no significant differences between Gpc3 +/+ and −/ mice. Lungs from Gpc3 −/ mice, however, were disproportionally heavy at time of birth, weighing 28% more than their normal littermates (data not shown). Since this disproportionate overgrowth is only evident in newborn mice, we speculate that it is due to the accumulation of debris observed in the lungs after birth (Fig. 3). With regard to the kidneys, while those from E13.5 −/ embryos were disproportionally larger than kidneys from the normal littermates (see Fig. 7), comparison of weight at E16.5, E18.5, and P0 did not show a statistically significant disproportionate overgrowth. This may be explained by the observation that the medulla of the −/ kidneys begins to degenerate by E15.5, resulting in a reduction in whole kidney mass.


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)

Kidney development in the Gpc3 −/ mouse. Paraffin-embedded tissue sections were generated from fixed tissue isolated from +/+ and −/ mice. E12.0 sections were imaged at 200×. Bar, 37.5 μm. E13.5, E16.5, and E18.5 sections were imaged at 100×. Bar, 75 μm. At E12.0, branching of the ureteric bud is markedly enhanced in the −/ versus +/+ embryo (arrowheads). By E13.5, the −/ kidney is much larger than that of its +/+ littermate and consists of histologically normal ureteric bud and mesenchymal-derived tissue elements. While these mesenchymal-derived elements (glomeruli and tubules) are present in the cortex (C) of the E16.5 −/ and +/+ kidneys, they are disorganized in the −/ cortex and the −/ medulla (M) is relatively devoid of tubular structures. Cysts (Cy) are present in −/ medulla in an irregular pattern. At E18.5, these abnormalities persist in the −/ kidney and are accompanied by total absence of the medullary tubular patterning characteristic of the +/+ kidney.
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Related In: Results  -  Collection

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Figure 7: Kidney development in the Gpc3 −/ mouse. Paraffin-embedded tissue sections were generated from fixed tissue isolated from +/+ and −/ mice. E12.0 sections were imaged at 200×. Bar, 37.5 μm. E13.5, E16.5, and E18.5 sections were imaged at 100×. Bar, 75 μm. At E12.0, branching of the ureteric bud is markedly enhanced in the −/ versus +/+ embryo (arrowheads). By E13.5, the −/ kidney is much larger than that of its +/+ littermate and consists of histologically normal ureteric bud and mesenchymal-derived tissue elements. While these mesenchymal-derived elements (glomeruli and tubules) are present in the cortex (C) of the E16.5 −/ and +/+ kidneys, they are disorganized in the −/ cortex and the −/ medulla (M) is relatively devoid of tubular structures. Cysts (Cy) are present in −/ medulla in an irregular pattern. At E18.5, these abnormalities persist in the −/ kidney and are accompanied by total absence of the medullary tubular patterning characteristic of the +/+ kidney.
Mentions: To determine if GPC3-deficient mice exhibit overgrowth, as SGBS patients do, we compared the weight of Gpc3 −/, +/−, and +/+ littermates at different stages of embryonic development. Fig. 5 shows that the Gpc3 −/ mice were significantly heavier than the wild-type littermates at every time point analyzed. The overgrowth was greater at the time of birth, when the GPC3-deficient mice were ∼30% heavier than normal littermates. Heterozygotes displayed an intermediate size at all time points. When we compared heart, lung, and liver weight as percentage of body weight at different embryonic stages, we found no significant differences between Gpc3 +/+ and −/ mice. Lungs from Gpc3 −/ mice, however, were disproportionally heavy at time of birth, weighing 28% more than their normal littermates (data not shown). Since this disproportionate overgrowth is only evident in newborn mice, we speculate that it is due to the accumulation of debris observed in the lungs after birth (Fig. 3). With regard to the kidneys, while those from E13.5 −/ embryos were disproportionally larger than kidneys from the normal littermates (see Fig. 7), comparison of weight at E16.5, E18.5, and P0 did not show a statistically significant disproportionate overgrowth. This may be explained by the observation that the medulla of the −/ kidneys begins to degenerate by E15.5, resulting in a reduction in whole kidney mass.

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