The Role for Proteoglycans in Regulating Embryonic Patterning and Morphogenesis

Growth factors and morphogens regulate embryonic patterning, cell fate specification, cell migration and morphogenesis. The activity and behaviour of these signalling molecules is regulated in the extracellular space through interactions with proteoglycans. Proteoglycans are high molecular-weight proteins consisting of a core protein with covalently linked glycosasminoglycan (GAG) sidechains, which are thought to mediate proteoglycan-ligand interactions. UDP-glucose dehydrogenase (Ugdh) is an enzyme required for the biosynthesis of GAGs, and in its absence the cell cannot polymerize sidechains. Drosophila mutant embryos deficient for Ugdh activity exhibit abnormal Fgf, Wnt, and TGFĂ signalling and die during gastrulation, indicating a broad and critical role for proteoglycans during early embryonic development. Mouse Ugdh mutants also die at gastrulation, however, only FGF signalling appears disrupted. These findings suggested a possible divergence in the requirement for proteoglycans during Drosophila and mouse embryogenesis, and that vertebrates may have evolved alternative means of regulating Wnt and TGFĂ activity. To further examine the function of proteoglycans in vertebrate development, I have characterized a zebrafish mutant devoid of both maternal and zygotic Ugdh activity (MZjekyll). I demonstrate that MZjekyll mutant embryos display abnormal Fgf, Shh, and Wnt signalling activities, with concomitant defects in central nervous system patterning, cardiac ventricular fate specification and axial morphogenesis. Furthermore, I uncover a novel role for proteoglycans in left-right pattern formation. My findings resolve longstanding questions into the evolutionary conservation of Ugdh function and provide new mechanistic insights into the initiation of left-right asymmetry.

Department dc:contributor.department

Molecular and Medical Genetics

Year dc:date.issued

2014

Author dc:creator

• Superina, Simone

Advisor dc:contributor.advisor

• Ciruna, Brian G

• embryonic pattering
• left-right asymmetry
• proteoglycans
• UDP-glucose dehydrogenase
• zebrafish

Handle dc:identifier.uri

http://hdl.handle.net/1807/73803

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/73803