Repellent Guidance of Regenerating Optic Axons by Chondroitin Sulfate Glycosaminoglycans in Zebrafish

Abstract

We analyzed the role of chondroitin sulfate (CS) glycosaminoglycans, putative inhibitors of axonal regeneration in mammals, in the regenerating visual pathway of adult zebrafish. In the adult, CS immunoreactivity was not detectable before or after an optic nerve crush in the optic nerve and tract but was constitutively present in developing and adult nonretinorecipient pretectal brain nuclei, where CSs may form a boundary preventing regenerating optic fibers from growing into these inappropriate locations. Enzymatic removal of CSs by chondroitinase ABC after optic nerve crush significantly increased the number of animals showing erroneous growth of optic axons into the nonretinorecipient magnocellular superficial/ posterior pretectal nucleus (83% vs 42% in controls). In vitro, a substrate border of CSs, but not heparan sulfates, strongly repelled regenerating retinal axons from adult zebrafish. We conclude that CSs contribute to repellent axon guidance during regeneration of the optic projection in zebrafish.

Regeneration beyond the glial scar

“…, and there is minimal upregulation of CSPGs on reactive glia in cold-blooded species, with the exception of special regions where regeneration does not occur 64 …”

“…Expression of these CSPGs increases in the glial scar in the brain and spinal cord of mature animals [54][55][56] . Proteoglycans have been implicated as barriers to CNS axon extension in the developing roof plate of the spinal cord 57,58 , in the midline of the rhombencephalon and mesencephalon 59,60 , at the dorsal root entry zone (DREZ) 61 , in retinal pattern development 62,63 , and at the optic chiasm and distal optic tract 64,65 . Extensive work has demonstrated that CSPGs are extremely inhibitory to axon outgrowth in culture.…”

Bioactive Nanomaterials for Neural Engineering

“…In healthy adult perineuronal networks, they are involved in stabilization of synaptic plasticity (Hunanyan et al 2010 ). However, upregulated levels of CSPGs are known to increase glial scar in the mature spinal cord and brain (Becker and Becker 2002 ), and they inhibit neurite outgrowth extensively in vitro (Sharma et al 2012 ). They are upregulated within 24 h following injury and they remain at the injury site for months (McKeon et al 1999 ;Jones et al 2003 ).…”

Application of Chondroitin Sulfate Derivatives for Understanding Axonal Guidance in the Nervous System during Development

“…The CS chains consist of repeating disaccharide units of glucuronic acid (GlcA) and N-acetylgalactosamine (GalNAc), forming straight chains of 20-200 units, with sulfate groups at various positions on the sugar chains. In many cases, effects of CS inhibit axonal outgrowth [11][12][13][14][15][16][17][18][19][20][21]. For example, if the central nervous system is damaged in higher vertebrates, CS is accumulated in glial scar tissue, inhibiting axonal growth to prevent the axons from rewiring their pathway.…”