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Developmental cell biology

Heparan sulphate proteoglycans: the sweet side of development

Nature Reviews Molecular Cell Biology volume 6, pages 530–541 (2005)Cite this article

Key Points

  • Heparan sulphate proteoglycans (HSPGs) are cell-surface or extracellular matrix glycoproteins that are modified by the addition of one or several glycosaminoglycan (GAG) chains.

  • GAGs are long unbranched polysaccharide chains that consist of repeating disaccharide units incorporating an amino sugar and a uronic acid.

  • Genetic studies in invertebrate and vertebrate model systems have identified HSPGs as important modulators of signal transduction pathways during development. Mutations in genes that encode proteoglycan core proteins or in genes that are involved in the biosynthesis of GAGs cause loss of activity in the Wnt, Hedgehog (Hh), Decapentaplegic (Dpp)/transforming growth factor-β (TGFβ) and fibroblast growth factor signalling pathways during development.

  • Glypicans and syndecans are HSPG core proteins that have been shown to mediate HSPG function during developmental signalling. Glypicans modulate the activity of the Wnt, Hh and Dpp/TGFβ pathways during embryonic development and patterning of imaginal discs in Drosophila melanogaster. Syndecans regulate the activity of the Slit–Robo pathway during axon pathfinding.

  • HSPGs modulate the tissue distribution of secreted signalling molecules in a concentration-dependent fashion by binding and concentrating morphogens — signalling molecules that form protein gradients and activate target genes in a concentration-dependent fashion — at the cell surface. In the absence of functional HSPGs, signalling molecules are lost from the cell surface and morphogen gradients are disrupted, which results in the loss of target-gene activation.

  • The function of HSPGs in different signalling pathways is core-protein specific and can be locally regulated by shedding from the cell surface. Proteoglycan core proteins are expressed in a tissue-specific fashion that correlates with their specific function in different signal transduction pathways.

Abstract

Pattern formation during development is controlled to a great extent by a small number of conserved signal transduction pathways that are activated by extracellular ligands such as Hedgehog, Wingless or Decapentaplegic. Genetic experiments have identified heparan sulphate proteoglycans (HSPGs) as important regulators of the tissue distribution of these extracellular signalling molecules. Several recent reports provide important new insights into the mechanisms by which HSPGs function during development.

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Figure 1: Biosynthesis of heparan sulphate, chondroitin sulphate or dermatan sulphate glycosaminoglycans.
Figure 2: Structure of membrane heparan sulphate proteoglycans.
Figure 3: Drosophila melanogaster genes involved in synthesis and modification of heparan sulphate.
Figure 4: Function of glypicans in growth factor signalling.
Figure 5: Heparan sulphate proteoglycans and Wingless morphogen activity gradients.

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Acknowledgements

Work in the Perrimon laboratory is supported by the Howard Hughes Medical Institute and the NIH. Work in the Häcker laboratory is supported by the Swedish Research Council VR and the Swedish Cancer Foundation.

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Authors and Affiliations

  1. Department of Experimental Medical Science, Lund Center for Stem Cell Biology and Cell Therapy, Lund University, Klinikgatan 26, BMC B13, Lund, 22184, Sweden

    Udo Häcker

  2. Department of Genetics, Harvard Medical School, Howard Hughes Medical Institute, 77 Avenue Louis Pasteur, Boston, 02175, Massachusetts, USA

    Kent Nybakken & Norbert Perrimon

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DATABASES

Entrez Gene

glypican 4

Flybase

botv

dally

dll

dlp

dpp

frc

Hh

notum

patched

Robo

sfl

sgl

Slit

sotv

ssl

trol

ttv

Wg

OMIM

Ehlers–Danlos syndrome

multiple hereditary exostosis

Simpson–Golabi–Behmel syndrome

Glossary

PATTERN FORMATION

The developmental processes by which the complex shape and structure of higher organisms occur.

EXTRACELLULAR MATRIX

The complex, multi-molecular material that surrounds cells. The extracellular matrix comprises a scaffold on which tissues are organized, it provides cellular microenvironments and it regulates many cellular functions.

GLYCOSAMINOGLYCAN

A long, linear, charged polysaccharide that comprises a repeating pair of sugars, of which one is an amino sugar.

AMINO SUGAR

A monosaccharide or its derivative in which an alcoholic hydroxyl group has been replaced by an amino group.

EPIMERIZATION

The process by which an epimer is converted into its diastereoisomer by altering the configuration at the epimeric chiral centre.

WILMS' TUMOUR

A malignant tumour of the kidney that occurs in children.

PROGEROID

Associated with premature ageing.

GPI ANCHOR

The function of this post-translational modification is to attach proteins to the exoplasmic leaflet of membranes, possibly to specific domains therein. The anchor is made of one molecule of phosphatidylinositol to which a carbohydrate chain is linked through the C-6 hydroxyl of the inositol, and is linked to the protein through an ethanolamine phosphate moiety.

TYPE I TRANSMEMBRANE PROTEIN

A protein that contains a single membrane-spanning domain, with the C terminus orientated towards the cytoplasm and the N terminus orientated towards the lumen of membrane compartments or in an extracellular direction.

SEGMENT POLARITY

The segmented patterning of the body along the anterior–posterior axis. Segment polarity genes are expressed in a pattern of 14 stripes at the onset of gastrulation and follow the expression of pair-rule genes.

GAL4/UAS SYSTEM

Used in D. melanogaster to target the expression of specific genes to specific tissues. UAS stands for the upstream-activating system of the yeast GAL4 gene.

WING IMAGINAL DISCS

Imaginal discs are the larval precursors of adult structures. The wing imaginal discs give rise to the dorsal thorax and the wing appendages.

CHONDROCYTE

A differentiated cell of cartilage tissue.

HYPOMORPHIC

A mutation that reduces, but does not completely eliminate, the function of a gene.

SOMATIC CLONES

A group of non-germline cells produced by proliferation of a single common ancestor cell.

RNA-MEDIATED INTERFERENCE (RNAi)

A form of post-transcriptional gene silencing in which expression or transfection of double-stranded RNA induces nuclease-mediated degradation of the homologous endogenous transcripts. This mimics the effect of the reduction, or loss, of gene activity.

PAIR-RULE GENE

A class of segmentation gene that determines segments along the anterior–posterior axis. The expression of pair-rule genes in a pattern of seven stripes that are perpendicular to the axis is regulated by another class of segmentation genes: the gap genes.

NON-CELL-AUTONOMOUS

A gene functions non-automonously if expression of the gene in one cell influences the phenotype of a different cell.

MESODERM

The third embryonic layer generated during gastrulation, which occupies an intermediate position between the ectoderm and the endoderm. It will develop into the skeleton, muscles and connective tissue.

GASTRULATION

A series of morphogenetic movements observed during the early development of most animals that leads to the formation of a multilayered embryo with an outer cell layer (ectoderm), an inner cell layer (endoderm) and an intermediate cell layer (mesoderm).

MORPHOLINO

A chemically modified oligonucleotide that behaves as an antisense RNA analogue and that is used to interfere with gene function.

TRANSHETEROZYGOUS COMBINATIONS

A combination of alleles of the same or different genes located on different homologous or non-homologous chromosomes.

GENE TRAP

A DNA construct that contains a reporter gene sequence downstream of a splice acceptor site that can integrate into random chromosomal locations in mouse. Integration of the gene trap into an intron allows the expression of a new mRNA containing one or more upstream exons followed by the reporter gene.

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Häcker, U., Nybakken, K. & Perrimon, N. Heparan sulphate proteoglycans: the sweet side of development. Nat Rev Mol Cell Biol 6, 530–541 (2005). https://doi.org/10.1038/nrm1681

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