title: 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.
authors.affiliation: Genentech, South San Francisco, CA 94080, USA.
authors.forename: Deanna G
authors.initials: DG
authors.lastname: Wilson
authors.forename: Khanhky
authors.initials: K
authors.lastname: Phamluong
authors.forename: Wei Yu
authors.initials: WY
authors.lastname: Lin
authors.forename: Kai
authors.initials: K
authors.lastname: Barck
authors.forename: Richard A D
authors.initials: RA
authors.lastname: Carano
authors.forename: Lauri
authors.initials: L
authors.lastname: Diehl
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Peterson
authors.forename: Flavius
authors.initials: F
authors.lastname: Martin
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Solloway
mesh_terms: D000818:Animals; D019521:Body Patterning; D015519:Bone Density; D001846:Bone Development; D001842:Bone and Bones / Q000201:enzymology*; D059327:Brachydactyly / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D017353:Gene Deletion; D014453:Glucuronosyltransferase; D016695:Glycosyltransferases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007596:Joints / Q000196:embryology*; D051379:Mice; D064251:Multifunctional Enzymes; D017350:N-Acetylgalactosaminyltransferases; D011247:Pregnancy
chemical_list: D064251:Multifunctional Enzymes; D016695:Glycosyltransferases; D017350:N-Acetylgalactosaminyltransferases; D014453:Glucuronosyltransferase; C571290:Chsy1 protein, mouse