Tissue inhibitor of metalloproteinase-2(TIMP-2)-deficient mice display motor deficits.
The degradation of the extracellular matrix is regulated by matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). Matrix components of the basement membrane play critical roles in the development and maintenance of the neuromuscular junction (NMJ), yet almost nothing is known about the regulation of MMP and TIMP expression in either the pre- or postsynaptic compartments. Here, we demonstrate that TIMP-2 is expressed by both spinal motor neurons and skeletal muscle. To determine whether motor function is altered in the absence of TIMP-2, motor behavior was assessed using a battery of tests (e.g., RotaRod, balance beam, hindlimb extension, grip strength, loaded grid, and gait analysis). TIMP-2(-/-) mice fall off the RotaRod significantly faster than wild-type littermates. In addition, hindlimb extension is reduced and gait is both splayed and lengthened in TIMP-2(-/-) mice. Motor dysfunction is more pronounced during early postnatal development. A preliminary analysis revealed NMJ alterations in TIMP-2(-/-) mice. Juvenile TIMP-2(-/-) mice have increased nerve branching and acetylcholine receptor expression. Adult TIMP-2(-/-) endplates are enlarged and more complex. This suggests a role for TIMP-2 in NMJ sculpting during development. In contrast to the increased NMJ nerve branching, cerebellar Purkinje cells have decreased neurite outgrowth. Thus, the TIMP-2(-/-) motor phenotype is likely due to both peripheral and central defects. The tissue specificity of the nerve branching phenotype suggests the involvement of different MMPs and/or extracellular matrix molecules underlying the TIMP-2(-/-) motor phenotype.
Jaworski
Diane M
DM
Department of Anatomy & Neurobiology, University of Vermont College of Medicine, Burlington, 05405, USA. diane.jaworski@uvm.edu
Soloway
Paul
P
Caterina
John
J
Falls
William A
WA
D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D015152:Blotting, Northern / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D002038:Bungarotoxins / Q000378:metabolism; D064026:Calbindins; D002490:Central Nervous System / Q000254:growth & development / Q000378:metabolism; D004622:Embryo, Mammalian; D005684:Gait / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D007150:Immunohistochemistry / Q000379:methods; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics; D024510:Muscle Development / Q000235:genetics; D009132:Muscles / Q000378:metabolism; D016900:Neurofilament Proteins / Q000378:metabolism; D009468:Neuromuscular Diseases / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011597:Psychomotor Performance / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D045442:Rotarod Performance Test / Q000379:methods; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000172:deficiency*
D002038:Bungarotoxins; D064026:Calbindins; D016900:Neurofilament Proteins; D012333:RNA, Messenger; D064030:S100 Calcium Binding Protein G; C051774:neurofilament protein H; D019716:Tissue Inhibitor of Metalloproteinase-2; D010751:Phosphopyruvate Hydratase