Avian neural crest cell migration is diversely regulated by the two major hyaluronan-binding proteoglycans PG-M/versican and aggrecan

Abstract

It has been proposed that hyaluronan-binding proteoglycans play an important role as guiding cues during neural crest (NC) cell migration, but their precise function has not been elucidated. In this study, we examine the distribution, structure and putative role of the two major hyaluronan-binding proteoglycans, PG-M/versicans and aggrecan, during the course of avian NC development. PG-M/versicans V0 and V1 are shown to be the prevalent isoforms at initial and advanced phases of NC cell movement, whereas the V2 and V3 transcripts are first detected following gangliogenesis. During NC cell dispersion, mRNAs for PG-M/versicans V0/V1 are transcribed by tissues lining the NC migratory pathways, as well as by tissues delimiting nonpermissive areas. Immunohistochemistry confirm the deposition of the macromolecules in these regions and highlight regional differences in the density of these proteoglycans. PG-M/versicans assembled within the sclerotome rearrange from an initially uniform distribution to a preferentially caudal localization, both at the mRNA and protein level. This reorganization is a direct consequence of the metameric NC cell migration through the rostral portion of the somites. As suggested by previous in situ hybridizations, aggrecan shows a virtually opposite distribution to PG-M/versicans being confined to the perinotochordal ECM and extending dorsolaterally in a segmentally organized manner eventually to the entire spinal cord at axial levels interspacing the ganglia. PG-M/versicans purified from the NC migratory routes are highly polydispersed, have an apparent M(r) of 1,200-2,000 kDa, are primarily substituted with chondroitin-6-sulfates and, upon chondroitinase ABC digestion, are found to be composed of core proteins with apparent M(r)of 360–530, 000. TEM/rotary shadowing analysis of the isolated PG-M/versicans confirmed that they exhibit the characteristic bi-globular shape, have core proteins with sizes predicted for the V0/V1 isoforms and carry relatively few extended glycosaminoglycan chains. Orthotopical implantation of PG-M/versicans immobilized onto transplantable micromembranes tend to ‘attract’ moving cells toward them, whereas similar implantations of a notochordal type-aggrecan retain both single and cohorts of moving NC cells in close proximity of the implant and thereby perturb their spatiotemporal migratory pattern. NC cells fail to migrate through three-dimensional collagen type I-aggrecan substrata in vitro, but locomote in a haptotactic manner through collagen type I-PG-M/versican V0 substrata via engagement of HNK-1 antigen-bearing cell surface components. The present data suggest that PG-M/versicans and notochordal aggrecan exert divergent guiding functions during NC cell dispersion, which are mediated by both their core proteins and glycosaminoglycan side chains and may involve ‘haptotactic-like’ motility phenomena. Whereas aggrecan defines strictly impenetrable embryonic areas, PG-M/versicans are central components of the NC migratory pathways favoring the directed movement of the cells.

How the extracellular matrix shapes neural development

“…They include brevican, neurocan, versican and aggrecan, of which versican has been shown to inhibit neural crest cell migration in Xenopus embryos [91]. This is consistent with findings in the developing chick embryo that both versican and aggrecan regulate neural crest cell migration [92].…”

Keratan sulfate (KS)‐proteoglycans and neuronal regulation in health and disease: the importance ofKS‐glycodynamics and interactive capability with neuroregulatory ligands

“…Versican and aggrecan differentially regulate neural cell migration, with the former providing positive migratory cues while aggrecan inhibits this process (Perissinotto et al . ; Perris and Perissinotto ). Neural cells also express CD44 and RHAMM which are active participants in neural cell migration, differentiation, and synaptic plasticity (Lynn et al .…”

“…This involves aggrecan HNK-1 mediated cellular interactions and N-terminal mediated interactions of the aggrecan G1 HA binding domain with HA in the ECM. Versican and aggrecan differentially regulate neural cell migration, with the former providing positive migratory cues while aggrecan inhibits this process (Perissinotto et al 2000;Perris and Perissinotto 2000). Neural cells also express CD44 and RHAMM which are active participants in neural cell migration, differentiation, and synaptic plasticity (Lynn et al 2001;Oohashi et al 2015;Roszkowska et al 2016;Miyata and Kitagawa 2017;Su et al 2017).…”

Mimicking biological phenomena in hydrogel-based biomaterials to promote dynamic cellular responses

“…For example, neural crest cells will migrate significantly faster on versican-containing matrix than aggrecan-containing matrix. 45 In some cases, as in epiblastic cell movement during primitive streak formation, cells can 'carry' their ECM along their migration. 46 Thus, the ECM is not set in its location as it is also not set in its composition and mechanical properties.…”