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© The Rockefeller University Press, 0021-9525/1999//255 $5.00
The Journal of Cell Biology, Volume 146, Number 1, , 1999 255-264

Original Article

Glypican-3–Deficient Mice Exhibit Developmental Overgrowth and Some of the Abnormalities Typical of Simpson-Golabi-Behmel Syndrome



Danielle F. Cano-Gaucia,b, Howard H. Songb,c, Huiling Yangb,c, Colin McKerliec, Barbara Chooa,b, Wen Shib,c, Rose Pullanoa,b, Tino D. Piscioned, Silviu Grisarud, Shawn Soond, Larisa Sedlackovad, A. Keith Tanswelld, Tak W. Maka,e, Herman Yegerd, Gina A. Lockwooda,b, Norman D. Rosenblumd, and Jorge Filmusb,c

a The Ontario Cancer Institute, Toronto, Ontario, M5G 2M9 Canada
b Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
c Sunnybrook Health Science Centre, Toronto, Ontario, M4N 3M5 Canada
d Hospital for Sick Children, Toronto, Ontario, M5G 1X8 Canada
e The Amgen Institute, Toronto, Ontario, M5G 2C1 Canada
Division of Cancer Biology Research, S-218 Research Building, Sunnybrook Health Science Centre, 2075 Bayview Avenue, Toronto, Ontario, M4N 3M5 Canada.(416) 480-5703(416) 480-6100

filmus{at}srcl.sunnybrook.utoronto.ca

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.

Key Words: glypican-3 • Simpson-Golabi-Behmel syndrome • overgrowth • insulin-like growth factor II • kidney dysplasia

© 1999 The Rockefeller University Press

1.used in this paper: BrdU, 5 bromo-2'deoxyuridine; BWS, Beckwith-Wiedemann syndrome; DBA, Dolichos biflorus agglutinin; E, embryonic day; ES, embryonic stem; GPC1, glypican-1; GPC3, glypican-3; HS, heparan sulfate; IGF-II, insulin-like growth factor II; IGF2R, IGF receptor type 2; P, postnatal day; SGBS, Simpson-Golabi-Behmel syndrome

This paper is dedicated to the memory of Ronald N. Buick.


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