title: Mice lacking the extracellular matrix protein WARP develop normally but have compromised peripheral nerve structure and function.
abstract: WARP is a recently identified extracellular matrix molecule with restricted expression in permanent cartilages and a distinct subset of basement membranes in peripheral nerves, muscle, and the central nervous system vasculature. WARP interacts with perlecan, and we also demonstrate here that WARP binds type VI collagen, suggesting a function in bridging connective tissue structures. To understand the in vivo function of WARP, we generated a WARP-deficient mouse strain. WARP-null mice were healthy, viable, and fertile with no overt abnormalities. Motor function and behavioral testing demonstrated that WARP-null mice exhibited a significantly delayed response to acute painful stimulus and impaired fine motor coordination, although general motor function was not affected, suggesting compromised peripheral nerve function. Immunostaining of WARP-interacting ligands demonstrated that the collagen VI microfibrillar matrix was severely reduced and mislocalized in peripheral nerves of WARP-null mice. Further ultrastructural analysis revealed reduced fibrillar collagen deposition within the peripheral nerve extracellular matrix and abnormal partial fusing of adjacent Schwann cell basement membranes, suggesting an important function for WARP in stabilizing the association of the collagenous interstitial matrix with the Schwann cell basement membrane. In contrast, other WARP-deficient tissues such as articular cartilage, intervertebral discs, and skeletal muscle showed no detectable abnormalities, and basement membranes formed normally. Our data demonstrate that although WARP is not essential for basement membrane formation or musculoskeletal development, it has critical roles in the structure and function of peripheral nerves.
authors.affiliation: Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria 3052, Australia.
authors.forename: Justin M
authors.initials: JM
authors.lastname: Allen
authors.forename: Laura
authors.initials: L
authors.lastname: Zamurs
authors.forename: Bent
authors.initials: B
authors.lastname: Brachvogel
authors.forename: Ursula
authors.initials: U
authors.lastname: Schlötzer-Schrehardt
authors.forename: Uwe
authors.initials: U
authors.lastname: Hansen
authors.forename: Shireen R
authors.initials: SR
authors.lastname: Lamandé
authors.forename: Lynn
authors.initials: L
authors.lastname: Rowley
authors.forename: Jamie
authors.initials: J
authors.lastname: Fitzgerald
authors.forename: John F
authors.initials: JF
authors.lastname: Bateman
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D024142:Collagen Type VI / Q000235:genetics / Q000378:metabolism*; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D016326:Extracellular Matrix Proteins; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics; D041641:Musculoskeletal Development / Q000235:genetics; D009928:Organ Specificity / Q000235:genetics; D010525:Peripheral Nerves / Q000378:metabolism* / Q000648:ultrastructure; D012583:Schwann Cells / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D024142:Collagen Type VI; D016326:Extracellular Matrix Proteins; C460761:WARP protein, mouse