Fmr1-knockout (Fmr1-KO) mice may be useful for studying behavioral and synaptic abnormalities associated with Fragile X Syndrome.
William T. Greenough, Beckman Institute
|Allele Type||Gene Symbol||Gene Name|
|Targeted||Fmr1||fragile X mental retardation syndrome 1|
|Allele Type||Gene Symbol||Gene Name|
|Not Applicable||Pde6b||phosphodiesterase 6B, cGMP, rod receptor, beta polypeptide|
|Allele Type||Gene Symbol||Gene Name|
This Fmr1 knockout is also available on a C57BL/6 genetic background: B6.129P2-Fmr1tm1Cgr/J (Stock No. 003025).
These mice have a knockout allele of the fragile X mental retardation syndrome 1 gene (Fmr1) on the X chromosome. Fmr1-knockout mice (homozygous females and hemizygous males) show many phenotypic characteristics of the Fragile X Syndrome in humans that lack the fragile X mental retardation protein (FMRP) as a result of a mutation in the FMR1 gene. FMRP is an RNA binding protein whose function is shown to be involved in translational regulation of specific dendritic mRNAs. Certain regions of the brain in these mice are characterized by the presence of long, thin dendritic spines on excitatory neurons.
Behavioral traits include deficits in classical delay eye-blink conditioning, autistic-like core symptoms of altered social interaction and occurrence of repetitive behaviors with additional hyperactivity, reduced anxiety, and increased errors in a learning assay. Whole-cell patch-clamp recordings in the anterior cingulate cortex show that long-term potentiation is completely abolished. A similar decrease in long-term potentiation is found in the lateral amygdala, another structure along with the anterior cingulate cortex implicated in fear memory. Failure of the startle response to develop after 4th postnatal week is seen.
Cellular defects include abnormalities in neurogenesis that are seen in the embryonic FMRP-deficient brain; neural progenitors accumulate abnormally in the subventricular zone of the embryonic neocortex.
Fmr1-knockout (Fmr1-KO) mice exhibit abnormalities of dendritic spines in multiple regions of the brain; absence of FMRP induces an over-activation of RAC1, a protein of the Rho GTPase subfamily that plays a critical role in dendritic morphology and synaptic function. Inhibitory synaptic abnormalities in the amygdala as a result of defective GABAergic neurotransmission have also been reported.
The absence of FMRP also causes defects of protein synthesis-dependent plasticity seen as an impairment of long-term potentiation in the cortex and hippocampus, as well as an augmentation of long-term depression in the hippocampus and cerebellum. Presynaptic abnormalities at excitatory hippocampal synapses in the knock-out mice also lead to defects in short-term plasticity and information processing.
Studies of Fmr1-knockout have revealed that over-activation of class I metabotropic glutamate receptor signaling is a primary defect in the cerebral cortex and hippocampus affecting synaptic plasticity. Enhanced tyrosine kinase B (TrkB) expression and brain derived neurotrophic factor (BDNF)-induced intracellular calcium responses in cortical neural progenitor cells lacking FMRP as well as changes in the expression of TrkB are seen in embryonic Fmr1-KO mice. Mammalian target of rapamycin (mTOR) phosphorylation and activity are elevated in the hippocampus of juvenile Fmr1-KO mice. Brains from Fmr1-KO mice display higher levels of reactive oxygen species, nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase activation, lipid peroxidation and protein oxidation than brains from wild-type mice.
Fmr1-knockout mice are viable and fertile. These mice possess the wildtype Pde6b allele and do not suffer from blindness due to retinal degeneration. Expected coat color is pigmented (gray) as the mice carry the Tyrc-ch allele (chinchilla). This mutant mouse strain has proven useful in studies related to Fragile X Syndrome.
The Fmr1-knockout (Fmr1-KO) targeting vector was designed to disrupt exon 5 of the fragile X mental retardation syndrome 1 locus (Fmr1) on the X chromosome with a neomycin resistance cassette. The construct was electroporated into 129P2/OlaHsd-derived E14 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6 blastocysts. Mice were backcrossed for 11 generations onto the FVB background, and are homozygous for the 129P2/OlaHsd wildtype Pde6b allele. this strain also has the Tyrc-ch allele (chinchilla).
|Allele Name||targeted mutation 1, Ben Oostra|
|Allele Type||Targeted (Null/Knockout)|
|Allele Synonym(s)||FMRP KO; Fmr1 KO; Fmr1tm4Cgr; FraX; fmr-tm1Cgr|
|Gene Symbol and Name||Fmr1, fragile X mental retardation syndrome 1|
|Gene Synonym(s)||FMRP; FRAXA; Fmr-1; Fmr-1; POF; POF1|
|Strain of Origin||129P2/OlaHsd|
|General Note||Genbank: AF179463 and AF170530|
|Molecular Note||A neomycin resistance gene was inserted into exon 5. RT-PCR analysis on testis RNA derived from hemizygous male mice demonstrated that no detectable transcript was produced from this allele, and western blot analysis on extracts of testes, liver, kidneyand brain of hemizygous male mice confirmed that no stable encoded protein was made.|
|Mutations Made By|| |
Ben Oostra, Erasmus University
|Allele Name||wild type|
|Allele Type||Not Applicable|
|Gene Symbol and Name||Pde6b, phosphodiesterase 6B, cGMP, rod receptor, beta polypeptide|
|Gene Synonym(s)||CSNB3; CSNBAD2; PDEB; Pdeb; Pdeb; RP40; nmf137; phosphodiesterase, cGMP, rod receptor, beta polypeptide; r; r; rd; rd; rd-1; rd1; rd1; rd10; rd10; retinal degeneration; retinal degeneration 1; retinal degeneration 10|
|Strain of Origin||Not Applicable|
|Allele Synonym(s)||cch; cr|
|Gene Symbol and Name||Tyr, tyrosinase|
|Gene Synonym(s)||ATN; C; CMM8; OCA1; OCA1A; OCAIA; Oca1; SHEP3; albino; c; skc35; skc35; skin/coat color 35|
|Strain of Origin||fancier's stock|
|Molecular Note||The mutation in the chinchilla allele was found to be a G to A point mutation that results in an amino acid change at position 464 from alanine to threonine.|
These mice have a knockout allele of the fragile X mental retardation syndrome 1 gene (Fmr1) on the X chromosome. This strain is maintained by breeding Fmr1-knockout mice together (i.e., homozygous females are bred with hemizygous males) are viable and fertile. Fmr1-knockout mice are viable and fertile. These mice possess the wildtype Pde6b allele and do not suffer from blindness due to retinal degeneration. Expected coat color is pigmented (gray) as the mice carry the Tyrc-ch allele (chinchilla).
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