Analysis of maternal-zygotic ugdh mutants reveals divergent roles for HSPGs in vertebrate embryogenesis and provides new insight into the initiation of left-right asymmetry.
Growth factors and morphogens regulate embryonic patterning, cell fate specification, cell migration, and morphogenesis. The activity and behavior of these signaling molecules are regulated in the extracellular space through interactions with proteoglycans (Bernfield et al., 1999; Perrimon and Bernfield 2000; Lander and Selleck 2000; Selleck 2000). Proteoglycans are high molecular-weight proteins consisting of a core protein with covalently linked glycosaminoglycan (GAG) side chains, which are thought to mediate ligand interaction. Drosophila mutant embryos deficient for UDP-glucose dehydrogenase activity (Ugdh, required for GAG synthesis) exhibit abnormal Fgf, Wnt and TGFß signaling and die during gastrulation, indicating a broad and critical role for proteoglycans during early embryonic development (Lin et al., 1999; Lin and Perrimon 2000) (Hacker et al., 1997). Mouse Ugdh mutants also die at gastrulation, however, only Fgf signaling appears disrupted (Garcia-Garcia and Anderson, 2003). These findings suggested a possible divergence in the requirement for proteoglycans during Drosophila and mouse embryogenesis, and that mammals may have evolved alternative means of regulating Wnt and TGFß activity. To further examine the function of proteoglycans in vertebrate development, we have characterized zebrafish mutants devoid of both maternal and zygotic Ugdh/Jekyll activity (MZjekyll). We demonstrate that MZjekyll mutant embryos display abnormal Fgf, Shh, and Wnt signaling activities, with concomitant defects in central nervous system patterning, cardiac ventricular fate specification and axial morphogenesis. Furthermore, we uncover a novel role for proteoglycans in left-right pattern formation. Our findings resolve longstanding questions into the evolutionary conservation of Ugdh function and provide new mechanistic insights into the initiation of left-right asymmetry.
Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, Ont., Canada M5G 1X8; Department of Molecular Genetics, The University of Toronto, Toronto, Ont., Canada M5S 1A8.
Simone
S
Superina
Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, Ont., Canada M5G 1X8; Department of Molecular Genetics, The University of Toronto, Toronto, Ont., Canada M5S 1A8.
Antonia
A
Borovina
Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, Ont., Canada M5G 1X8; Department of Molecular Genetics, The University of Toronto, Toronto, Ont., Canada M5S 1A8. Electronic address: ciruna@sickkids.ca.
Brian
B
Ciruna
D000818:Animals; D019521:Body Patterning / Q000235:genetics*; D004330:Drosophila / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000378:metabolism; D047108:Embryonic Development / Q000235:genetics*; D005346:Fibroblast Growth Factors / Q000378:metabolism; D054262:Gastrulation / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D006025:Glycosaminoglycans / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism; D019812:Heparan Sulfate Proteoglycans / Q000235:genetics / Q000378:metabolism*; D059446:Heterotaxy Syndrome / Q000235:genetics*; D051379:Mice; D011509:Proteoglycans / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014533:Uridine Diphosphate Glucose Dehydrogenase / Q000235:genetics*; D051153:Wnt Proteins / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D015053:Zygote
D029721:Drosophila Proteins; D006025:Glycosaminoglycans; D053823:Hedgehog Proteins; D019812:Heparan Sulfate Proteoglycans; D011509:Proteoglycans; C578287:Shh protein, Drosophila; D016212:Transforming Growth Factor beta; D051153:Wnt Proteins; D005346:Fibroblast Growth Factors; D014533:Uridine Diphosphate Glucose Dehydrogenase
Embryonic patterning; Left–right asymmetry; Proteoglycans; UDP-glucose dehydrogenase; Zebrafish