Abstract
The correct migration and axon extension of neurons in the developing nervous system is essential for the appropriate wiring and function of neural networks. Here, we report that O-sulfotransferases, a class of enzymes that modify heparan sulfate proteoglycans (HSPGs), are essential to regulate neuronal migration and axon development. We show that the 6-O-sulfotransferases HS6ST1 and HS6ST2 are essential for cranial axon patterning, whilst the 2-O-sulfotransferase HS2ST (also known as HS2ST1) is important to regulate the migration of facial branchiomotor (FBM) neurons in the hindbrain. We have also investigated how HS2ST interacts with other signals in the hindbrain and show that fibroblast growth factor (FGF) signalling regulates FBM neuron migration in an HS2ST-dependent manner.
Highlights
Various developmental processes require heparan sulfate proteoglycans (HSPGs), extracellular matrix proteins with covalently linked polysaccharide side chains that are polymerised by exotosin enzymes and further modified by sulfation, epimerisation or deacetylation to generate vast structural and functional heterogeneity (Kreuger and Kjellen, 2012)
Hs6st1 and Hs6st2 cooperate in cranial axon guidance, but are dispensable for facial branchiomotor (FBM) neuron migration To examine whether HSPGs regulate FBM neuron migration, we used an ex vivo hindbrain culture assay (Fig. 1A)
The inclusion of heparitinase in the culture medium to remove heparan sulfate side chains from HSPGs (Linhardt et al, 1990) prevented FBM neuron migration beyond r5 (Fig. 1B). This observation suggested that HSPGs are important for FBM neuron migration
Summary
Various developmental processes require heparan sulfate proteoglycans (HSPGs), extracellular matrix proteins with covalently linked polysaccharide side chains that are polymerised by exotosin enzymes and further modified by sulfation, epimerisation or deacetylation to generate vast structural and functional heterogeneity (Kreuger and Kjellen, 2012). We show that mice lacking HS6ST1 and HS6ST2 have defective axon extension of specific branches of the Vth and VIIth cranial nerves, but normal FBM neuron migration. Mice lacking HS2ST showed normal cranial axon patterning, but had FBM neuron migration defects similar to those seen in mice lacking VEGF signalling through NRP1.
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