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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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Histological analysis of wild-type (+/+) and GPC3 deficient (−/) lungs. Hematoxylin and eosin stained sections of lungs at E18, P0, and P5 are shown. Accumulation of mucus (arrowhead) and cellular debris (arrow) is indicated. Original magnification is 400.
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Figure 3: Histological analysis of wild-type (+/+) and GPC3 deficient (−/) lungs. Hematoxylin and eosin stained sections of lungs at E18, P0, and P5 are shown. Accumulation of mucus (arrowhead) and cellular debris (arrow) is indicated. Original magnification is 400.

Mentions: As discussed above, a proportion of Gpc3 −/ mice survived beyond the first day, particularly in earlier backcrosses (N2 to N4). Many of these mice, however, died before weaning. Histological analysis revealed the presence of bacterial infection in the respiratory tract (pneumonia and rhinitis), as well as an accumulation of cellular debris and mucus in small and medium size bronchioles. Although there were no obvious differences between wild-type and mutant mice at E18 (embryonic day 18; Fig. 3), as early as P0 (postnatal day 0) the lumens of airways contained an admixture of stranding mucus and sloughed epithelial cells. By P5, the amount of mucus had increased and was distributed over the entire surface of the respiratory epithelium. These lesions may have contributed to the perinatal death and increased susceptibility of Gpc3 −/ mice to respiratory infections.


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)

Histological analysis of wild-type (+/+) and GPC3 deficient (−/) lungs. Hematoxylin and eosin stained sections of lungs at E18, P0, and P5 are shown. Accumulation of mucus (arrowhead) and cellular debris (arrow) is indicated. Original magnification is 400.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 3: Histological analysis of wild-type (+/+) and GPC3 deficient (−/) lungs. Hematoxylin and eosin stained sections of lungs at E18, P0, and P5 are shown. Accumulation of mucus (arrowhead) and cellular debris (arrow) is indicated. Original magnification is 400.
Mentions: As discussed above, a proportion of Gpc3 −/ mice survived beyond the first day, particularly in earlier backcrosses (N2 to N4). Many of these mice, however, died before weaning. Histological analysis revealed the presence of bacterial infection in the respiratory tract (pneumonia and rhinitis), as well as an accumulation of cellular debris and mucus in small and medium size bronchioles. Although there were no obvious differences between wild-type and mutant mice at E18 (embryonic day 18; Fig. 3), as early as P0 (postnatal day 0) the lumens of airways contained an admixture of stranding mucus and sloughed epithelial cells. By P5, the amount of mucus had increased and was distributed over the entire surface of the respiratory epithelium. These lesions may have contributed to the perinatal death and increased susceptibility of Gpc3 −/ mice to respiratory infections.

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