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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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Mandibular hypoplasia in Gpc3 −/ embryos. Alizarin red/Alcian blue skeletal preparations of wild-type (top) and Gpc3 −/ (bottom) E18.5 embryonic heads are shown. Note the complete lack of mandible in the mutant embryo.
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Figure 4: Mandibular hypoplasia in Gpc3 −/ embryos. Alizarin red/Alcian blue skeletal preparations of wild-type (top) and Gpc3 −/ (bottom) E18.5 embryonic heads are shown. Note the complete lack of mandible in the mutant embryo.

Mentions: In our initial examination of the newborn Gpc3 −/ mice, no obvious skeletal abnormalities were observed by X-ray analysis or staining. However, when mutant embryos from backcrosses N7 and N8 were examined, a proportion of them (10%) were found to have severe mandibular hypoplasia (Fig. 4). Histological analysis of jaw sections revealed no bone constituting the rami of the mandible, which consisted only of myxomatous stroma with overlying haired skin (data not shown).


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)

Mandibular hypoplasia in Gpc3 −/ embryos. Alizarin red/Alcian blue skeletal preparations of wild-type (top) and Gpc3 −/ (bottom) E18.5 embryonic heads are shown. Note the complete lack of mandible in the mutant embryo.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 4: Mandibular hypoplasia in Gpc3 −/ embryos. Alizarin red/Alcian blue skeletal preparations of wild-type (top) and Gpc3 −/ (bottom) E18.5 embryonic heads are shown. Note the complete lack of mandible in the mutant embryo.
Mentions: In our initial examination of the newborn Gpc3 −/ mice, no obvious skeletal abnormalities were observed by X-ray analysis or staining. However, when mutant embryos from backcrosses N7 and N8 were examined, a proportion of them (10%) were found to have severe mandibular hypoplasia (Fig. 4). Histological analysis of jaw sections revealed no bone constituting the rami of the mandible, which consisted only of myxomatous stroma with overlying haired skin (data not shown).

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