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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 kidney sections. Kidney sections from 4-d-old wild-type (top) and GPC3-deficient (bottom) littermates were fixed and sections stained with hematoxylin and eosin.
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Figure 2: Histological analysis of kidney sections. Kidney sections from 4-d-old wild-type (top) and GPC3-deficient (bottom) littermates were fixed and sections stained with hematoxylin and eosin.

Mentions: Anatomical examination of mice from N4 and successive backcrosses revealed the presence of cystic and dysplastic kidneys in all Gpc3 −/ and some female Gpc3 +/− mice (Fig. 2). These abnormalities were seen in a large proportion of mice from earlier backcrosses, also. However, the degree of dysplasia varied significantly from mouse to mouse.


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 kidney sections. Kidney sections from 4-d-old wild-type (top) and GPC3-deficient (bottom) littermates were fixed and sections stained with hematoxylin and eosin.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 2: Histological analysis of kidney sections. Kidney sections from 4-d-old wild-type (top) and GPC3-deficient (bottom) littermates were fixed and sections stained with hematoxylin and eosin.
Mentions: Anatomical examination of mice from N4 and successive backcrosses revealed the presence of cystic and dysplastic kidneys in all Gpc3 −/ and some female Gpc3 +/− mice (Fig. 2). These abnormalities were seen in a large proportion of mice from earlier backcrosses, also. However, the degree of dysplasia varied significantly from mouse to mouse.

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