Drosophila heparan sulfate proteoglycans

(First version published:March.15, 2001)

The genetically tractable model organism, Drosophila melanogaster, continues to be an excellent system to study the molecular mechanisms by which heparan sulfate proteoglycans (HSPGs) regulate cell signaling.  In addition to serving as co-receptors that modulate signaling, it has more recently been found that HSPGs regulate the distributions of extracellular signaling molecules, such as morphogens and axon guidance cues.

(A) A morphogen is secreted from its source (right side of the square) and forms concentration gradients in the developmental field. (B) The shape of the morphogen gradient is altered in mutants for HSPG core protein genes or HS biosynthetic genes. This example shows a gradient shortened by such a mutation as seen for the Dpp gradient in Drosophila dally mutant wing discs. (C) In some cases, the gradient extends in a mutant background. For example, a partial reduction of HS synthesis results in an extended range of Indian Hedgehog signaling during mouse chondrocyte differentiation.

Morphogens are signaling molecules that form concentration gradients in the developmental field and specify different cell fates at distinct concentrations.  These molecules provide a fundamental mechanism of generating patterns during tissue assembly, and are involved in many disease processes.  Despite their important roles in development, it is poorly understood how morphogen gradients are established and maintained.  Analyses of mutations in genes for Drosophila HSPG core proteins and HS biosynthetic enzymes showed that HSPGs are critical for signaling as well as distributions of morphogen molecules such as Decapentaplegic (Dpp), Wingless (Wg), and Hedgehog (Figure 1; 1, 2).  For example, Dally, a member of the glypican family of HSPGs, affects the shape of the Dpp morphogen gradient in the developing wing.  The second Drosophila glypican, Dally-like (Dlp) controls Wg distributions, serving to limit the domain of Wg signaling.

Another class of secreted molecules whose distribution is controlled by HSPGs is axon guidance cues (3).  During neuronal development, specialized glial cells secrete attractive and repulsive cues to regulate growth cone navigation at the midline of the central nervous system.  The secreted repellent Slit and its axonal receptors in the Roundabout (Robo) family regulate distance of axons from the midline in many organisms.  Recent studies revealed that Drosophila syndecan (sdc) is expressed on axons in the ventral nerve cord, and that sdc mutants show a midline-crossing defect.  Sdc forms complexes with Slit and Robo, and the extracellular distribution of Slit is altered in sdc mutants.  These observations indicated that Sdc regulates axon guidance by modulating distribution of Slit, the main repellant at the midline.

Recent genetic studies using the Drosophila model have also addressed fundamental questions regarding the molecular basis underlying HSPG functions.  One such question was the relative contribution of HS chains and the core protein to the function of a HSPG (2).  To assess the importance of HS modification for in vivo activities of a particular proteoglycan, a mutant form of Dally, which is not HS modified, was generated and its signaling activity was evaluated.  In vivo expression studies and rescue experiments using the mutant form demonstrated that significant functional capacity resides in the protein core.

Hiroshi Nakato (Department of Genetics, Cell Biology and Development, University of Minnesota)
References(1) Tabata and Takei (2004) Morphogens, their identification and regulation.  Development 131, 703-712
(2) Kirkpatrick and Selleck (2007) The varied functions of heparan sulfate proteoglycans.  J. Cell Sci. (in press)
(3) Lee and Chien (2004) When sugars guide axons: insights from heparan sulphate proteoglycan mutants.  Nat. Rev. Genet. 5, 923-935.
March.2, 2007

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