4 research outputs found
The FMR1 CGG repeat mouse displays ubiquitin-positive intranuclear neuronal inclusions; implications for the cerebellar tremor/ataxia syndrome
Recent studies have reported that alleles in the premutation range in the
FMR1 gene in males result in increased FMR1 mRNA levels and at the same
time mildly reduced FMR1 protein levels. Some elderly males with
premutations exhibit an unique neurodegenerative syndrome characterized by
progressive intention tremor and ataxia. We describe neurohistological,
biochemical and molecular studies of the brains of mice with an expanded
CGG repeat and report elevated Fmr1 mRNA levels and intranuclear
inclusions with ubiquitin, Hsp40 and the 20S catalytic core complex of the
proteasome as constituents. An increase was observed of both the number
and the size of the inclusions during the course of life, which correlates
with the progressive character of the cerebellar tremor/ataxia syndrome in
humans. The observations in expanded-repeat mice support a direct role of
the Fmr1 gene, by either CGG expansion per se or by mRNA level, in the
formation of the inclusions and suggest a correlation between the presence
of intranuclear inclusions in distinct regions of the brain and the
clinical features in symptomatic premutation carriers. This mouse model
will facilitate the possibilities to perform studies at the molecular
level from onset of symptoms until the final stage of the disease
Instability of a (CGG)98 repeat in the Fmr1 promoter
Fragile X syndrome is one of 14 trinucleotide repeat diseases. It arises
due to expansion of a CGG repeat which is present in the 5'-untranslated
region of the FMR1 gene, disruption of which leads to mental retardation.
The mechanisms involved in trinucleotide repeat expansion are poorly
understood and to date, transgenic mouse models containing transgenic
expanded CGG repeats have failed to reproduce the instability seen in
humans. As both cis-acting factors and the genomic context of the CGG
repeat are thought to play a role in expansion, we have now generated a
knock-in mouse Fmr1 gene in which the murine (CGG)8 repeat has been
exchanged with a human (CGG)98 repeat. Unlike other CGG transgenic models,
this model shows moderate CGG repeat instability upon both in maternal and
paternal transmission. This model will now enable us to study the timing
and the mechanism of repeat expansion in mice
Fxr1 knockout mice show a striated muscle phenotype: implications for Fxr1p function in vivo.
FXR1 is one of the two known homologues of FMR1. FXR1 shares a high degree
of sequence homology with FMR1 and also encodes two KH domains and an RGG
domain, conferring RNA-binding capabilities. In comparison with FMRP, very
little is known about the function of FXR1P in vivo. Mouse knockout (KO)
models exist for both Fmr1 and Fxr2. To study the function of Fxr1 in
vivo, we generated an Fxr1 KO mouse model. Homozygous Fxr1 KO neonates die
shortly after birth most likely due to cardiac or respiratory failure.
Histochemical analyses carried out on both skeletal and cardiac muscles
show a disruption of cellular architecture and structure in E19 Fxr1
neonates compared with wild-type (WT) littermates. In WT E19 skeletal and
cardiac muscles, Fxr1p is localized to the costameric regions within the
muscles. In E19 Fxr1 KO littermates, in addition to the absence of Fxr1p,
costameric proteins vinculin, dystrophin and alpha-actinin were found to
be delocalized. A second mouse model (Fxr1 + neo), which expresses
strongly reduced levels of Fxr1p relative to WT littermates, does not
display the neonatal lethal phenotype seen in the Fxr1 KOs but does
display a strongly reduced limb musculature and has a reduced life span of
approximately 18 weeks. The results presented here point towards a role
for Fxr1p in muscle mRNA transport/translation control similar to that
seen for Fmrp in neuronal cells
Knockout mouse model for Fxr2: a model for mental retardation
Fragile X syndrome is a common form of mental retardation caused by the
absence of the FMR1 protein, FMRP. Fmr1 knockout mice exhibit a phenotype
with some similarities to humans, such as macro-orchidism and behavioral
abnormalities. Two homologs of FMRP have been identified, FXR1P and FXR2P.
These proteins show high sequence similarity, including all functional
domains identified in FMRP, such as RNA binding domains. They have an
overlap in tissue distribution to that of FMRP. Interactions between the
three FXR proteins have also been described. FXR2P shows high expression
in brain and testis, like FMRP. To study the function of FXR2P, we
generated an Fxr2 knockout mouse model. No pathological differences
between knockout and wild-type mice were found in brain or testis. Given
the behavioral phenotype in fragile X patients and the phenotype
previously reported for the Fmr1 knockout mouse, we performed a thorough
evaluation of the Fxr2 knockout phenotype using a behavioral test battery.
Fxr2 knockout mice were hyperactive (i.e. traveled a greater distance,
spent more time moving and moved faster) in the open-field test, impaired
on the rotarod test, had reduced levels of prepulse inhibition, displayed
less contextual conditioned fear, impaired at locating the hidden platform
in the Morris water task and were less sensitive to a heat stimulus.
Interestingly, there are some behavioral phenotypes in Fxr2 knockout mice
which are similar to those observed in Fmr1 knockout mice, but there are
also some different behavioral abnormalities that are only observed in the
Fxr2 mutant mice. The findings implicate a role for Fxr2 in central
nervous system function