Knockdown of chondroitin‐4‐sulfotransferase‐1, but not of dermatan‐4‐sulfotransferase‐1, accelerates regeneration of zebrafish after spinal cord injury

Abstract

Glycosaminoglycans such as chondroitin sulfate (CS) and dermatan sulfate (DS) are long chains of repeating disaccharide units, covalently linked to core proteins to form proteoglycans. Proteoglycans can be cell membrane‐bound or are part of the extracellular matrix. They are important in a wide range of biologic processes, including development, synaptic plasticity, and regeneration after injury, as well as modulation of growth factor signaling, cell migration, survival, and proliferation. Synthesis of CS and DS in the Golgi apparatus is mediated by sulfotransferases that modify sugar chains through transfer of sulfate groups to specific positions on the sugar moieties. To clarify the functions of CS and DS during nervous system regeneration, we studied the effect of chondroitin 4‐O‐sulfotransferase‐1/carbohydrate sulfotransferase‐11 (C4ST‐l/Chst‐11) and dermatan 4‐O‐sulfotransferase‐1/Chst‐14 (D4ST‐l/Chst‐14) down‐regulation on spinal cord regeneration in larval and adult zebrafish. In our study, knockdown of C4ST1/Chst‐11 accelerated regeneration after spinal cord injury in larval and adult zebrafish and knockdown of D4ST1/Chst‐14 did not alter regenerative capacity. From these and previous observations, we drew the conclusion that different CS and DS expression patterns can be growth permitting, growth inhibiting, or neutral for regrowing or sprouting axons, depending on the tissue environment of a particular animal species.—Sahu, S., Li, R., Loers, G., Schachner, M. Knockdown of chondroitin‐4‐sulfotransferase‐l, but not of dermatan‐4‐sulfotransferase‐l, accelerates regeneration of zebrafish after spinal cord injury. FASEB J. 33, 2252–2262 (2019). http://www.fasebj.org

Extracellular matrix remodeling with stress and depression: Studies in human, rodent and zebrafish models

“…Of interest, zebrafish express sulfotransferases that may influence the sensitivity of PNN components to proteolysis (Habicher et al., 2015; Sahu, Li, Loers, & Schachner, 2019). Knockdown of chondroitin‐4‐sulfotransferase in zebrafish, which generates neuroplasticity‐restricting 4‐sulfated chondroitin sulfate‐glycosaminoglycans in rodents (Foscarin, Raha‐Chowdhury, Fawcett, & Kwok, 2017), accelerates regeneration following spinal cord injury (Sahu et al., 2019). This result is consistent with conserved mechanisms by which ECM affects neuroplasticity in diverse organisms.…”

Building bridges, not walls: spinal cord regeneration in zebrafish

“…ECM remodeling is thought to be crucial for functional recovery from SCI; for instance, in mice, ECM proteins such as CSPGs are upregulated after injury and can inhibit the growth of axons (Dyck and Karimi-Abdolrezaee, 2015). In zebrafish, morpholino knockdown of Chondroitin-4-sulfotransferase-1, a sulfotransferase important in the synthesis of CSPGs, enhanced the speed of spinal cord regeneration in both larvae and adults, suggesting that this mechanism is conserved between zebrafish and mouse (Sahu et al, 2019). After SCI in zebrafish, the expression of ostensibly growthpermissive ECM components (like Ctgfa) is induced in both neural and non-neural tissues within the injured spinal cord.…”

Operation spinal cord regeneration: Patterning information residing in extracellular matrix glycosaminoglycans

“…Furthermore, extracellular matrix from mouse limbs is capable of inducing limb pattern in axolotl blastemas in a position‐specific, developmental‐stage‐specific, and heparan sulfate‐dependent manner. Furthermore, Sahu et al demonstrated that knockdown of chondroitin‐4‐sulfotransferase‐1, but not of dermatan‐4‐sulfotransferase‐1, accelerates regeneration of zebrafish after spinal cord injury, indicating that chondroitin sulfate and dermatan sulfate structures play different roles in axonal regeneration (Sahu, Li, Loers, & Schachner, ). When using immunohistochemistry to examine the expression of two chondroitin sulfates with different sulfation variants at the lesion site in the spinal cord of goldfish, Takeda et al showed that chondroitin sulfate is co‐localized with the regenerating axons (Takeda, Okada, & Funakoshi, ).…”