Abstract
BackgroundHeparan sulfate (HS) is an ubiquitous component of the extracellular matrix that binds and modulates the activity of growth factors, cytokines and proteases. Animals with defective HS biosynthesis display major developmental abnormalities however the processes that are affected remain to be defined. D-glucuronyl-C5-epimerase (Glce) is a key HS chain modifying enzyme that catalyses the conversion of glucuronic acid into iduronic acid, a biosynthetic step that enhances HS biological activity. In this study the role of Glce during early zebrafish development has been investigated.ResultsTwo Glce-like proteins (Glce-A and -B) are expressed in zebrafish at all times. They are the products of two distinct genes that, based on chromosomal mapping, are both orthologues of the same single human gene. Transcripts for both proteins were detected in fertilized zebrafish embryos prior to the onset of zygotic transcription indicating their maternal origin. At later developmental stages the epimerases are expressed widely throughout gastrulation and then become restricted to the hindbrain at 24 h post-fertilization. By monitoring the expression of well characterized marker genes during gastrulation, we have found that misexpression of Glce causes a dose-dependent expansion of the ventral structures, whereas protein knockdown using targeted antisense morpholino oligonucleotides promotes axis dorsalization. The ventralizing activity of Bmp2b is enhanced by Glce overexpression whereas Glce knockdown impairs Bmp2b activity.ConclusionGlce activity is an important determinant of of dorso-ventral axis formation and patterning in zebrafish. In particular Glce acts during gastrulation by affecting Bmp-mediated cell specification. The results obtained further corroborate the concept that HS encodes information that affect morphogenesis during early vertebrate development.
Highlights
Heparan sulfate (HS) is an ubiquitous component of the extracellular matrix that binds and modulates the activity of growth factors, cytokines and proteases
In this paper we report that Glce's activity affects the establishment of the embryonic dorso-ventral (D/V) axis through a mechanism involving the bone morphogenetic proteins (Bmps)
The results obtained corroborate the concept that HS encodes information that directs morphogenesis during early vertebrate development
Summary
Heparan sulfate (HS) is an ubiquitous component of the extracellular matrix that binds and modulates the activity of growth factors, cytokines and proteases. D-glucuronyl-C5-epimerase (Glce) is a key HS chain modifying enzyme that catalyses the conversion of glucuronic acid into iduronic acid, a biosynthetic step that enhances HS biological activity. Heparan sulfate proteoglycans (HSPG) are macromolecules found in all connective tissues, extracellular matrices and on the surface of cells [1]. Their most prominent feature is the presence of one or more heparan sulfate (HS). HS is composed of repeating disaccharide units of D-glucuronic acid (GlcA) or L-iduronic acid (IdoA) both of which may be 2O-sulfated, and unsubstituted, N-acetylated, or N-, 3O- or 6O-sulfated glucosamine (Glc). Typical HS chains contain relatively short segments of modified sequences represented by IdoA-GlcNS derivatives of different sulfation content dispersed among large sections of unmodified (GlcA-GlcNAc) units
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