We report in this paper that GPC3-deficient mice exhibit several of the clinical features of SGBS patients, including developmental overgrowth, perinatal death, cystic and dysplastic kidneys, and abnormal lung development. Other abnormalities observed in some SGBS patients, such as hernias, heart defects, polydactyly, and vertebral and rib malformations, are not present in the mutant mice. Conversely, GPC3-deficient mice display mandibular hypoplasia and an imperforate vagina, two clinical features that have not been described in SGBS patients. It is interesting to note that an imperforate vagina could be the result of deficient apoptosis of the vaginal epithelial cells during sexual maturation (Jacobson et al. 1997
). This is consistent with our recent finding that GPC3 can induce apoptosis in certain cell types (Dueñas Gonzalez et al. 1998
Although not all the clinical features observed in SGBS patients are found in the GPC3-deficient mice, we consider that there are enough similarities to justify the use of these mice as a model to study SGBS. In particular, these mice will be useful to study the role of GPC3 in the regulation of growth during development. Indeed, we are reporting here that Gpc3
−/ mice display hyperplasia of the developing ureteric bud/collecting duct system. Most likely this hyperplasia explains, at least in part, the cystic and dysplastic phenotype of the kidneys in the GPC3-deficient mice and SGBS patients. In addition, the GPC3-deficient mice will be useful to study the role of GPC3 in lung development. In this respect, it is interesting to note that SGBS patients, like the Gpc3
−/ mice, also develop respiratory infections with high frequency (Garganta and Bodurtha 1992
The similarities between SGBS and BWS have suggested the hypothesis that GPC3 regulates IGF-II activity. Furthermore, the IGF2R-deficient mice display a degree of developmental overgrowth similar to the Gpc3
−/ mice. In contrast to the IGF2R
knockouts, however, the GPC3-deficient mice do not show any increase in circulating or local expression of IGF-II (). Moreover, we have been unable to detect direct interaction between GPC3 and IGF-II (Song et al. 1997
). It can be concluded, therefore, that if GPC3 inhibits IGF-II signaling, it does so by a mechanism that is fundamentally different than the one used by the IGF2R.
Eggenschwiler et al. 1997
have recently generated double mutant mice that exhibit a dramatic increase in circulating and tissue IGF-II. These investigators have proposed that, in addition to the clinical features of BWS, these mice display skeletal abnormalities typical of SGBS (). However, SGBS patients and GPC3-deficient mice display severe renal abnormalities, and no such abnormalities have been found in the double mutant mice, despite the fact that they express extremely high levels of IGF-II. Moreover, none of the other mice models that overexpress IGF-II (Igf-II
transgenics and Igf2R
knockouts) display any renal alterations. Thus, it is reasonable to propose that even if GPC3 is able to regulate IGF-II signaling, it may have other functions in addition to IGF-II regulation. In this regard, we have shown that GPC3 can bind fibroblast growth factor-2 (Song et al. 1997
), and others have demonstrated that GPC1 can regulate the response of several cell types to heparin-binding growth factors (Steinfeld et al. 1996
; Kleef et al. 1998
). Since these interactions are mediated by the glypicans' HS chains, it is possible that GPC3 interacts with other factors that are known to bind to HS, including members of the transforming growth factor-β and Wnt families. Interestingly, some members of these families are known to play a role in kidney development (Vainio and Muller 1997
; Woolf and Cale 1997
Recently, it has been reported that ~5% of BWS patients show germline mutations of p57, a cyclin-dependent kinase inhibitor (Hatada et al. 1996
). In addition, it has been suggested that p57 can also be silenced at the transcriptional level in BWS patients without germline mutations (Lee et al. 1999
). Interestingly, p57-deficient mice show kidney dysplasia, adrenal cytomegaly, and omphalocele, but not overgrowth or other features of BWS patients (Zhang et al. 1997
; ). Since mice overexpressing IGF-II, unlike p57-deficient mice, do not show renal abnormalities, it has been proposed that suppression of p57 expression is a key contributor to the phenotype of BWS patients (Hastie 1997
). This raises the question as to whether p57 could be mediating some of the signals regulated by GPC3, and this issue should certainly be the subject of future investigations.
Given the complexity and heterogeneity of the phenotypic features of SGBS and BWS, we consider it unlikely that the role of the molecules suspected to be involved in the generation of these disorders will be resolved simply by genetic manipulation of mice (see ). It is evident that biochemical studies will be required to clarify the connection between the different molecules involved.