Correct establishment of the left/right (L/R) body asymmetry in the mouse embryo requires asymmetric activation of the evolutionarily conserved Nodal signaling cascade in the left lateral plate mesoderm (L-LPM). Furthermore, the presence of Nodal in the node is essential for its own expression in the L-LPM. Here, we have characterized the function of cerl-2, a novel Nodal antagonist, which displays a unique asymmetric expression on the right side of the mouse node. cerl-2 knockout mice display multiple laterality defects including randomization of the L/R axis. These defects can be partially rescued by removing one nodal allele. Our results demonstrate that Cerl-2 plays a key role in restricting the Nodal signaling pathway toward the left side of the mouse embryo by preventing its activity in the right side.Supplemental material is available at http://www.genesdev.org.

VEGF and TGF-β1 are cytokines that stimulate tissue invasion and angiogenesis. These factors are considered as molecular targets for the therapy of glioblastoma. Bevacizumab, a recombinant humanized monoclonal antibody developed against VEGF, inhibits endothelial cell proliferation and vessel formation. Flavonoids obtained from Dimorphandra mollis and Croton betulaster have been described as proliferation inhibitors of a human glioblastoma derived cell line. VEGF and TGF-β1 levels were dosed by ELISA in a GL-15 cell line treated with bevacizumab and also with the flavonoids rutin, 5-hydroxy-7,4'-dimethoxyflavone, casticin, apigenin and penduletin. Rutin reduced the VEGF and TGF-β1 levels after 24 h but not after 72 h. The other flavonoids significantly reduced TGF-β1 production. Bevacizumab reduced only the VEGF levels in the supernatant from GL-15 cultures. These results suggest that the flavonoids studied, and commonly used in popular medicine, present an interesting subject of study due to their potential effect as angiogenic factor inhibitors.

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12532 Background: Malignant gliomas are typically angiogenic and express greater amounts of angiogenic factors. Vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) are prominent glioblastoma-associated multifunctional cytokines that stimulate migration, invasion and angiogenesis. Their receptor inhibiton is considered an important target for anitumoral therapy. Flavonoids obtained from Dimorphandra mollis and Croton betulaster, native medicinal plants from Bahia-Brazil, have been described as proliferation inhibitors of a human glioblastoma derived cell line and reduce VEGF production by GL-15. In this study, VEGF and PDGF receptors expression by GL-15 cultures treated with bevacizumab and flavonoids were evaluated. Methods: GL-15 cultures were treated or not with pendulitin and rutin flavonoids (100μM) and bevacizumab (1μg/mL). After 24 hours VEGF and PDGF receptors were analyzed by flow cytometry using monoclonal antibodies labeled with FITC. Results: Flow cytometry showed that the GL-15 cells expressed PDGFR alfa (10%), PDGFR beta (52%), VEGFR 1 (26%) and VEGFR 2 (95%). It was observed that the pendulitin and rutin flavonoids treated cells showed a reduction on PDGFR alfa expression (2 and 1,6 % respectively) but the other receptors expression was similar to the non-treated or DMSO treated controls. Conclusions: GL-15 human glioblastoma derived cell line expresses receptors to the angiogenic cytokines studied. VEGFR 2 expression was predominant and bevacizumab didn’t alter the receptors production. Flavonoids extracted from D. mollis and C. betulaster seem to have an inhibitory action on the PDGRF alfa expression but not on the others receptors. No significant financial relationships to disclose.