OVER-EXPRESSION OF THE CHONDROITIN SULFATE PROTEOGLYCAN VERSICAN IS ASSOCIATED WITH DEFECTIVE NEURAL CREST MIGRATION IN THE PAX3 MUTANT MOUSE (SPLOTCH)

Splotch mice, which harbour mutations in the Pax3 gene, exhibit neural crest-related abnormalities including pigmentation defects, reduced o r absent dorsal root ganglia and failure of cardiac outflow tract sept ation in homozygotes. Although splotch neural crest cells fail to colo nise target tissues, they initiate migration in vivo and appear to mig rate as well as wild type neural crest cells in vitro, suggesting that the neural crest abnormality in splotch may reside not in the neural crest cells themselves, but rather in the extracellular environment th rough which they migrate. We have examined the expression of genes enc oding extracellular matrix molecules in Sp(2H) homozygous embryos and find a marked over-expression of transcripts for the chondroitin sulph ate proteoglycan versican in the pathways of neural crest cell migrati on. Use of cadherin-6 expression as a marker for neural crest demonstr ates a striking correlation between up-regulation of versican expressi on and absence of migrating neural crest cells, both in the mesenchyme lateral to the neural tube and in the lower branchial arches of Sp(2H ) homozygotes. Pax3 and versican have mutually exclusive expression pa tterns in normal embryos whereas, in Sp(2H) homozygotes, versican is g enerally over-expressed with 'infilling' in regions that would normall y express functional Pax3. Versican, like other chondroitin sulphate p roteoglycans, is non-permissive for migration of neural crest cells in vitro, and we suggest that over-expression of this molecule leads to the arrest of neural crest cell migration in splotch embryos. Pax3 may serve to negatively regulate versican expression during normal develo pment, thereby guiding neural crest cells into their pathways of migra tion. (C) 1997 Elsevier Science Ireland Ltd.