B6.129P2(SJL)-Ntrk1^tm1Ddg/J

Stock number: 022362
Research areas: Cell Biology Research, Neurobiology Research, Research Tools

Description

These mice carry a hypomorphic floxed F592A mutation in mouse Ntrk1 (neurotrophic tyrosine kinase, receptor, type 1; also called TrkA). Signaling is effectively blocked by application of 1NMPP1. This strain is useful in studies of nerve growth and survival.

Detailed description

Ntrk1 (neurotrophic tyrosine kinase, receptor, type 1; also called TrkA) is a receptor for nerve growth factor (Ngf), a neurotrophin which controls aspects of mammalian nervous system development. NGF-NTRK1 (NGF-TrkA) signaling is crucial for the survival and growth of sympathetic neurons as well as small-diameter nociceptive sensory neurons.

These mice carry a floxed F592A mutation in exon 12 of the mouse Ntrk1 gene. The allele is sensitive to a family of small-molecule inhibitors including 1NaPP1 and 1NMPP1 which act selectively, rapidly and reversibly. Without 1NaPP1 or 1NMPP1 application, homozygous mutant mice are hypomorphic, with an approximate 50% reduction of both the number of calcitonin gene-related peptide (CGRP) and Ret-positive neurons in dorsal root ganglion and a reduction of peripheral innervation of both sensory and sympathetic fibers. Although hypomorphic, the mutants are viable and fertile, and signaling is effectively blocked by application of 1NMPP1. In sympathetic neurons cultured from mutant mice, NGF-dependent survival is robustly and specifically blocked by nanomolar concentrations of 1NMPP1 or 1NaPP1. 1NMPP1 application during pregnancy leads loss of superior cervical ganglion neurons. 1NMPP1 treatment during adulthood leads to axon terminal degeneration of a selective group of small-diameter peptidergic sensory neurons.

Development

An F592A (phenylalanine to alanine) mutation was generated in exon 12 to disrupt an ATP binding pocket, and an FRT-flanked neomycin cassette was placed in intron 12. A segment including exons 7-12 and the neomycin cassette was flanked by loxP sites. The mutation was made in 129P2/OlaHsd-derived GK129 embryonic stem (ES) cells. Heterozygotes were bred with C57BL/6-backcrossed mice bearing Tg(ACTFLPe)9205Dym to excise the FRT-flanked neomycin cassette. This strain was backcrossed to C57BL/6 for approximately 6 generations by the donating lab.

Allele

Symbol: Ntrk1^tm1Ddg
Name: targeted mutation 1, David D Ginty
MGI accession ID: MGI:3583733
Generation method: Targeted
Attributes: Not Specified
Marker symbol: Ntrk1
Marker name: neurotrophic tyrosine kinase, receptor, type 1
Chromosome: 3
Strain of origin: 129P2/OlaHsd
Molecular note: A phenylalanine to alanine substitution mutation at residue 592 (F592A) was introduced via homologous recombination using a mutagenized construct with an FRT flanked neomycin resistance tag. Heterozygotes were bred with mice bearing Tg(ACTFLPe)9205Dym which expressed FLP1 recombinase. The resulting allele has the F592A mutation but the neomycin resistance cassete has been excised.