These mice are deficient in TIMP-2, tissue inhibitor of metalloproteinase 2, and exhibit locomotor impairment, abnormal fear conditioning behavior, and defective neuronal differentiation. This mutant mouse strain may be useful in studies of extracellular matrix homeostasis, synaptic plasticity in behavior, learning and memory, neuronal differentiation and development of neuromuscular junctions.
Paul D. Soloway, Cornell University
Mice that are homozygous for the targeted mutation are viable, fertile, normal in size and do not display any gross physical or behavioral abnormalities. No gene product (mRNA) is detected by Northern blot analysis of lung tissue. Mutant mice are unable to proteolytically activate proMMP-2, proenzyme matrix metalloproteinase-2. Male homozygotes exhibit deficits in fear-potentiated startle respnses and both male and female mutants exhibit reduced prepulse inhibition. Homozygotes exhibit muscle weakness (due to reduced mass of extensor digitorum longus fast-twitch muscle), decreased motor function, abnormal gait and reduced hindlimb extension. The brains of homozygotes in the postnatal week are smaller in size than wildtype controls, with the size difference disappearing after postnatal day 7. Histological analysis reveals abnormal neuromuscular junctions characterized by a larger size with increased nerve branching, reduced cerebellar cortex thickness, and reduced Purkinje cell processes. Homozygotes have impaired neuronal differentiation. Female homozygotes are passive when handled, while male homozygotes are aggressive. This mutant mouse strain may be useful in studies of extracellular matrix homeostasis, synaptic plasticity in behavior, learning and memory, neuronal differentiation and development of neuromuscular junctions.
A targeting vector containing PGKneo cassette was used to disrupt exon 1 and 5' flanking sequence. The construct was electroporated into 129S4/SvJae derived J1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts. The resulting chimeric animals were crossed to generate homozygous mice. The mice were then backcrossed to C57BL/6 J for 12 generations before arriving at The Jackson Laboratory.
|Allele Name||targeted mutation 1, Paul D Soloway|
|Allele Type||Targeted (Null/Knockout)|
|Allele Synonym(s)||Timp2-; TIMP2KO; TIMP-2KO|
|Gene Symbol and Name||Timp2, tissue inhibitor of metalloproteinase 2|
|Strain of Origin||129S4/SvJae|
|Molecular Note||Replacement of the first coding exon with a neomycin cassette.|
|Mutations Made By|| |
Paul Soloway, Cornell University
When maintaining a live colony, these mice can be bred as homozygotes.
When using the B6.129S4-Timp2tm1Pds/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #008120 in your Materials and Methods section.