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Review
. 2016 Jun;97(3):213-29.
doi: 10.1111/iep.12180. Epub 2016 Jul 6.

The role of heparan sulphate in development: the ectodermal story

Vivien Jane Coulson-Thomas  1
Affiliations
Review

The role of heparan sulphate in development: the ectodermal story

Vivien Jane Coulson-Thomas. Int J Exp Pathol. 2016 Jun.

Abstract

Heparan sulphate (HS) is ubiquitously expressed and is formed of repeating glucosamine and glucuronic/iduronic acid units which are generally highly sulphated. HS is found in tissues bound to proteins forming HS proteoglycans (HSPGs) which are present on the cell membrane or in the extracellular matrix. HSPGs influence a variety of biological processes by interacting with physiologically important proteins, such as morphogens, creating storage pools, generating morphogen gradients and directly mediating signalling pathways, thereby playing vital roles during development. This review discusses the vital role HS plays in the development of tissues from the ectodermal lineage. The ectodermal layer differentiates to form the nervous system (including the spine, peripheral nerves and brain), eye, epidermis, skin appendages and tooth enamel.

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Figures

Figure 1
Figure 1
Proposed model for the HSPG syndecan‐1 and HS structure. (a) The core protein of syndecan‐1 (blue) is immersed in a lipid DPPC membrane and HS (green carbon atoms) and CS (yellow carbon atoms) chains are attached to the extracellular domain at positions Ser37 (CS), Ser45 (HS) and Ser47 (HS). The structure of syndecan‐1 was modelled using MODELLER (Marti‐Renom et al. 2000) and the DPPC membrane, tetrasaccharide linkage region, and both HS and CS chains were added using charmm version c37b2 (Brooks et al. 2009). The highlighted box (b) is represented in more detail in (b). (b) A HS tetrasaccharide is shown in detail with carbon (green sticks), oxygen (red sticks), sulphate (yellow sticks) and nitrogen atoms (blue sticks). (c) Chemical structure of HS, which is comprised of repeating disaccharide units (GlcA or IdoA and GlcN). Putative sulphation and epimerization sites are highlighted in red.
Figure 2
Figure 2
Schematic of modifications on heparan sulphate chains by biosynthetic enzymes. HS is synthesized by sequential addition of alternating GlcA and GlcNAc by EXT1 and EXT2 respectively. Thereafter, a group of enzymes further modifies the HS chain: C5 epimerase epimerizes GlcA to IdoA, and the sulfotransferases NDST, 2‐OST, 3‐OST and 6‐OST add sulphate groups.
Figure 3
Figure 3
HS chemical and conformational structures. (A) The chemical structure of HS. HS is comprised of repeating disaccharide units (GlcA or IdoA and GlcN) and may display sulphated regions interspersed with unsulphated regions, creating specific domains, namely NS (N‐sulphated), NA (N‐acetylated) and NA/NS domains. (B) Electrostatic potential map of the structural domains of HS as calculated by APBS (Baker et al. 2001), demonstrating that the more negatively charged NS domain presents high electrostatic potential and the NA domain presents lower electrostatic potential (visualized as normalized volume contour at +12.0 kT/e in blue and −12.0 kT/e in red). Potential isosurfaces were visualized in VMD (Humphrey et al. 1996). (C) A representation of the crystallographic torsion angles φ–ψ of the glycosidic linkage of HS, which dictates the flexibility of the differently charged HS domains. The highly electrostatic NS domain (b) presents lower torsion angles in comparison with the less electrostatic NA domain which has higher torsion angles and is consequently more flexible than the NS domain (a) (Perkins et al. 2014). (D) Different HS domains after 20 ns molecular dynamics simulations show conformational changes of the HS domains over time revealing the reduced flexibility of NS domains in comparison with NA domains (supporting the unpublished data of Tarsis F. Gesteira). NA domains are represented as cyan sticks, NANS domains are represented as green sticks, and NS domains are represented in purple. The computer simulations and analysis were performed at the Ohio Supercomputer Center (OSC, 1987).
Figure 4
Figure 4
Loss of epidermal HS disrupts the distribution of morphogens. The knockout of Ext1 in keratin 14 expressing cells (Ext1 Δ/ΔEpi) leads to a loss of epidermal HS disrupting β‐catenin and SHH distribution at the epidermal–mesenchymal junction in comparison with wild‐type mice (wt). The epidermis (Epi), a sebaceous gland (SB), a hair follicle (HF) and the underlying dermis (*) are shown in the figure.
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