Chondroitin sulphate N-acetylgalactosaminyl-transferase-1 inhibits recovery from neural injury.
Extracellular factors that inhibit axon growth and intrinsic factors that promote it affect neural regeneration. Therapies targeting any single gene have not yet simultaneously optimized both types of factors. Chondroitin sulphate (CS), a glycosaminoglycan, is the most abundant extracellular inhibitor of axon growth. Here we show that mice carrying a gene knockout for CS N-acetylgalactosaminyltransferase-1 (T1), a key enzyme in CS biosynthesis, recover more completely from spinal cord injury than wild-type mice and even chondroitinase ABC-treated mice. Notably, synthesis of heparan sulphate (HS), a glycosaminoglycan promoting axonal growth, is also upregulated in TI knockout mice because HS-synthesis enzymes are induced in the mutant neurons. Moreover, chondroitinase ABC treatment never induces HS upregulation. Taken together, our results indicate that regulation of a single gene, T1, mediates excellent recovery from spinal cord injury by optimizing counteracting effectors of axon regeneration--an extracellular inhibitor of CS and intrinsic promoters, namely, HS-synthesis enzymes.
1] Department of Neurochemistry and Molecular Cell Biology, Brain Research Institute, Niigata University, 1-757 Asahi-machi, Niigata 951 8510, Japan [2] Center for Transdisciplinary Research, Brain Research Institute, Niigata University, 1-757 Asahi-machi, Niigata 951 8510, Japan.
Kosei
K
Takeuchi
Nozomu
N
Yoshioka
Susumu
S
Higa Onaga
Yumi
Y
Watanabe
Shinji
S
Miyata
Yoshino
Y
Wada
Chika
C
Kudo
Masayasu
M
Okada
Kentaro
K
Ohko
Kanako
K
Oda
Toshiya
T
Sato
Minesuke
M
Yokoyama
Natsuki
N
Matsushita
Masaya
M
Nakamura
Hideyuki
H
Okano
Kenji
K
Sakimura
Hitoshi
H
Kawano
Hiroshi
H
Kitagawa
Michihiro
M
Igarashi
D000818:Animals; D002809:Chondroitin Sulfates / Q000096:biosynthesis*; D015971:Gene Expression Regulation, Enzymologic; D051379:Mice; D018345:Mice, Knockout; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics / Q000378:metabolism*; D013119:Spinal Cord Injuries / Q000235:genetics / Q000378:metabolism*
D002809:Chondroitin Sulfates; D017350:N-Acetylgalactosaminyltransferases; C472559:chondroitin sulfate N-acetylgalactosaminyltransferase-1