STOCK Dock3^tm1Dasc/MsalxJ

Stock number: 033736
Product name: moca^-
Research areas: Neurobiology Research

Description

Moca^-/- mice have a lacZ sequence and a neo cassette replacing part of exon 2 of the dedicator of cyto-kinesis 3 (Dock3) gene. These mice are useful when studying axonal degeneration.

Detailed description

Moca^-/- mice have a lacZ sequence and a neo cassette replacing part of exon 2 of the dedicator of cyto-kinesis 3 (Dock3) gene. DOCK3, or Moca (modifier of cell adhesion) is a guanine nucleotide exchange factor expressed in neurons and testis that induces axonal outgrowth in the central nervous system (CNS) by activating the small G protein Rac1. MOCA regulates metabolism of cell adhesion proteins, such as amyloid precursor protein (APP) and N-cadherin, and is also involved in modulating neurite growth. MOCA is found in AD tangles and regulates tau phosphorylation. Mutations in the human MOCA gene have been linked to attention deficit hyperactivity disorder (ADHD) and Duchenne muscular dystrophy (DMD).

The absence of protein expression in these moca^-/- mice has been confirmed by western blot analysis on brain, spinal cord, pituitary, and testis extracts. They contain dystrophic axons associated with abnormal aggregates of neurofilament protein, the disorganization of the axonal cytoskeleton, and the accumulation of autophagic vacuoles and polyubiquitinated proteins. They also have defects in the actin cytoskeleton and the formation of cofilin-containing rod-like structures. Cofilin is an actin-depolymerizing factor involved in signaling pathways that disrupt the actin cytoskeleton.

Mice are viable and fertile, with normal lifespan, although the donating investigator observes a steep decline in fertility after 6 months due to neurological and muscle defects. Clinical features include gait abnormalities, limb weakness, ataxia, and an impaired ability to swim. The mutant mice also show spinning and clasping phenotypes when their tails are lifted.

Development

The moca^-/- targeting vector was designed to replace part of exon 2 of the dedicator of cyto-kinesis 3 (Dock3) gene, following the translation initiation site, with a lacZ sequence and a neo cassette. The construct was electroporated into embryonic stem (ES) cells of an unknown origin. Correctly targeted ES cells were injected into blastocysts and resulting chimeric mice were bred to C57BL/6J mice by the donating lab (see SNP note below). Subsequently, moca^-/- mice were backcrossed to C57BL/6J mice (Stock No. 000664) for at least six generations. Upon arrival, sperm was cryopreserved. To establish our live colony, an aliquot of frozen sperm was used to fertilize C57BL/6J oocytes.



A 48 SNP (single nucleotide polymorphism) panel analysis, with 43 markers covering all 19 chromosomes and the X chromosome, as well as 5 markers that distinguish between the C57BL/6J and C57BL/6N substrains, was performed on the rederived living colony at The Jackson Laboratory Repository. Three of the 43 markers throughout the genome were segregating with an unknown source on Chromosomes 9, 10, and 11. Also, 3 of the 5 markers that determine C57BL/6J from C57BL/6N were found to be segregating. These data suggest the mice sent to The Jackson Laboratory Repository were on a mixed C57BL/6N;C57BL/6J genetic background.

Allele

Symbol: Dock3^tm1Dasc
Name: targeted mutation 1, David Schubert
MGI accession ID: MGI:3831156
Generation method: Targeted
Attributes: Reporter; Null/Knockout
Synonyms: Moca^-
Marker symbol: Dock3
Marker name: dedicator of cyto-kinesis 3
Marker synonyms: Moca; NEDIDHA; PBP
Chromosome: 9
Strain of origin: Not Specified
Molecular note: Part of exon 2 following the translation initiation site was replaced with a lacZ and neo cassette. The absence of protein expression was confirmed by western blot analysis on brain, spinal cord, pituitary, and testis extracts.