Chondroitin sulfate synthase 1 (Chsy1) is required for bone development and digit patterning

Abstract

Joint and skeletal development is highly regulated by extracellular matrix (ECM) proteoglycans, of which chondroitin sulfate proteoglycans (CSPGs) are a major class. Despite the requirement of joint CSPGs for skeletal flexibility and structure, relatively little is understood regarding their role in establishing joint positioning or in modulating signaling and cell behavior during joint formation. Chondroitin sulfate synthase 1 (Chsy1) is one of a family of enzymes that catalyze the extension of chondroitin and dermatan sulfate glycosaminoglycans. Recently, human syndromic brachydactylies have been described to have loss-of-function mutations at the CHSY1 locus. In concordance with these observations, we demonstrate that mice lacking Chsy1, though viable, display chondrodysplasia and decreased bone density. Notably, Chsy1(-/-) mice show a profound limb patterning defect in which orthogonally shifted ectopic joints form in the distal digits. Associated with the digit-patterning defect is a shift in cell orientation and an imbalance in chondroitin sulfation. Our results place Chsy1 as an essential regulator of joint patterning and provide a mouse model of human brachydactylies caused by mutations in CHSY1.

Human Genetic Disorders and Knockout Mice Deficient in Glycosaminoglycan

“…Chsy1 -deficient mice are viable but exhibit chondrodysplasia, progression of the bifurcation of digits, delayed endochondral ossification, and reduced bone density [81]. Furthermore, a decrease in 4- O -sulfation and increase in 6- O -sulfation as well as desulfation of the GalNAc residues of CS have been reported in the cartilage of Chsy1 −/− mice.…”

“…Furthermore, a decrease in 4- O -sulfation and increase in 6- O -sulfation as well as desulfation of the GalNAc residues of CS have been reported in the cartilage of Chsy1 −/− mice. The signaling of hedgehog but not of FGF, bone morphogenetic protein, or transforming growth factor- β altered in primary chondrocytes from Chsy1-deficient mice [81], which suggests that CS-PGs and hedgehog protein may coordinately regulate skeletal development and digit patterning.…”

Metabolism of Cartilage Proteoglycans in Health and Disease

“…However, it has been revealed that knockout mice for either of ChSy-1 , ChPF, or ChGn-1 are viable and fertile, although they do synthesize reduced CS amounts with an imbalance in its sulfation [32–35]. Due to the decreased CS content and sulfation, especially in cartilaginous tissues, the animals display skeletal abnormalities including chondrodysplasia, decreased bone density, and digit-patterning defects.…”

Using Sugar Remodeling to Study Chondroitin Sulfate Function

“…Each of three single-gene knockouts ChSy-1 (Chsy1), ChPF (Chpf ), or ChGn-1 (Csgalnact1) result in viable, fertile mice, although each knockout genotype results in reduced CS production and/or a sulfation imbalance in CS chains. [24][25][26][27] Thus, to clarify the functions of CS in early mammalian embryogenesis, we focused on GlcAT-I (Fig. 1).…”