Knockout of the JAKMIP1 gene in mice resulted in reduced translation of PSD proteins, disrupted glutamatergic signaling, and autistic-like behaviors such as social deficits, stereotyped activity, and abnormal postnatal vocalizations (Berg et al., 2015). JAKMIP1 had previously been shown to be differentially expressed in lymphoblastoid cells from autistic males as well as in Fmr1 knockout-mice (Nishimura et al., 2007).
Molecular Function
The protein encoded by the JAKMIP1 gene associates with microtubules and may play a role in the microtubule-dependent transport of the GABA-B receptor. It also may play a role in JAK1 signaling and regulate microtubule cytoskeleton rearrangements.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
JAKMIP1, a Novel Regulator of Neuronal Translation, Modulates Synaptic Function and Autistic-like Behaviors in Mouse.
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Chimeras were produced from Velocigene embryonic stem cells in which Jakmip1 coding exons 28 were replaced with a LacZ-Neo cassette by homologous recombination.
Allele Type: Targeted(Knock-Out)
Strain of Origin: C57BL/6
Genetic Background: C57BL/6
ES Cell Line: Velocigene embryonic stem cells in which Jakmip1 coding exons 28 were replaced with a LacZ-Neo cassette
Mutant ES Cell Line: Not Specified
Model Source: Not Specified
Description: Jakmip1 ko mice show impaired motor coordination and decreased strength.
Exp Paradigm: Latency to fall from the rotarod measured; maximum time of trial 180 s; p values calculated using a two-tailed unpaired t test; males and females tested-accelerating rotarod test
Description: Jakmip1 ko mice show impaired motor coordination and decreased strength.
Exp Paradigm: Latency to fall from the rotarod measured; maximum time of trial 180 s; p values calculated using a two-tailed unpaired t test; males and females tested- wire hang test
Description: Over 90% penetrance of grooming in jakmip1 ko mice, mouse analogs of restrictive and repetitive behaviors observed in asd
Exp Paradigm: Behavior recorded by automated system top scan over 10 minute period; videos scored blinded to genotype for grooming; grooming was defined by repetitive cleaning of body and face; males and females tetsed
Description: Total volume, cortex, caudate putamen, and cerebellar volume are decreased in jakmip1 ko mice; absence of a strain by age effect in any of the structures analyzed indicates that this is most likely developmental microcephaly rather than neurodegeneration
Exp Paradigm: Live scan imaging
Description: Total volume, cortex, caudate putamen, and cerebellar volume are decreased in jakmip1 ko mice compared to controls, indicative of developmental microcephaly
Exp Paradigm: Live scan imaging
Description: The proportion of striatal medium sized spiny neurons (msns) showing ampa and nmda currents, showed a greater nmdar-mediated response in jakmip1 ko than wt mice; the charge and decay time are significantly increased compared to wt responses in postnatal jakmip1 ko msns;
Exp Paradigm: Ampa receptor antagonist nbqx (10m) was included in the external solution when recording nmdar-mediated responses; holding potential of -70 mv
Description: Glutamatergic signaling was disrupted in jakmip1 ko mice compared to control
Exp Paradigm: Coronal slices of postnatal and adult male mice were used; whole-cell patch-clamp was recorded in voltage clamp mode; for evoked synaptic currents, stimulating electrode was placed in the corpus callosum 300m from the recorded cell
Synaptic neuroreceptor ratio (nmdar/ampar) dependent transmission1
Decreased
Description: A proportion of jakmip1 ko striatal dorsolateral medium-sized spiny neurons (msns) (postnatal 25%, adult 16%) showing an ampar-mediated response failed to display an nmdar-mediated response, whereas all wt msns responded
Exp Paradigm: Coronal slices of postnatal and adult male mice were used; whole-cell patch-clamp was recorded in voltage clamp mode; for evoked synaptic currents, stimulating electrode was placed in the corpus callosum 300m from the recorded cell
Description: Charge of inward ampa current was significantly increased in jakmip1 ko msns compared to wt msns due to an increased duration of the slowly desensitizing component
Exp Paradigm: Coronal slices of postnatal and adult male mice were used; whole-cell patch-clamp was recorded in voltage clamp mode; for evoked synaptic currents, stimulating electrode was placed in the corpus callosum 300m from the recorded cell
Description: Over 90% penetrance of repetetive jumping in jakmip1 ko mice, mouse analogs of restrictive and repetitive behaviors observed in asd; this behavior is mediated by the striatal glutamatergic system
Exp Paradigm: Behavior recorded by automated system top scan over 10 minute period; videos scored blinded to genotype for grooming; grooming was defined by repetitive cleaning of body and face; males and females tetsed
Description: Jakmip1 ko mice buried fewer marbles than wt mice; consistent with the decreased anxiety suggested by performance in the light-dark box
Exp Paradigm: 12 marbles were placed equidistantly in a 3x4 grid; number of marbles that were buried more than two thirds into the bedding were counted and one photograph was taken for each cage to verify results
Description: Jakmip1 ko mice show increased perseveration in the t maze; significantly fewer alterations than wt mice
Exp Paradigm: T maze spontaneous alternation test; chi-squared test on the number of overall choices of left or right; no bias in arm choice observed; males and females tetsed
Description: Social dysfunction in jakmip1 ko mice is not due to disrupted olfaction
Exp Paradigm: Behavior was recorded by the automated system, top scan; males and females tested; distance traveled and average velocity over a 20 minute recording period measured in open field test-three-chamber social approach test
Description: Social dysfunction in jakmip1 ko mice is not due to disrupted olfaction
Exp Paradigm: Behavior was recorded by the automated system, top scan; males and females tested; distance traveled and average velocity over a 20 minute recording period measured in open field test- open field test
Description: Jakmip1 ko mice showed an increased time to return to huddle; loss of jakmip1 disrupts striatal nmdar signaling, contributing to the disruption of their behavior
Exp Paradigm: Measured time to return to huddle; test run blinded to genotype; males and females tested
Description: Jakmip1 ko mice showed a significant increase in postnatal ultrasonic vocalizations in various call types across all time points, unrelated to body weight, compared to wt controls upon separation from their mother
Exp Paradigm: Pups were separated from their mother and placed in a sound proof chamber; recording room was heated; usvs were recorded for 5 minutes using avisoft software (berlin, germany); mice were weighed after testing and returned to the home cage; mice were tested and scored blinded to genotype
Description: Jakmip1 ko mice spent more time in the light compartment compared to the dark compartment, showed a significant reduction of latency to enter the light compartment, increased border crossings suggestive of either reduced anxiety or increased impulsivity
Exp Paradigm: Number of cross overs between light and dark chambers was recorded by the automated system, top scan; males and females tested
Cued or contextual fear conditioning: memory of cue1
Decreased
Description: Jakmip1 ko mice showed reduced noise-cued fear response, indicative of a potential disruption of auditory-amygdala circuits
Exp Paradigm: Shock intensity 0.5 ma, shock duration was two seconds; tone intensity 80db, tone length 30 seconds, tone frequency 2000 hertz (hz); mice were allowed 30 minutes to habituate to the room before trials
Description: Psd95 protein level decreased in jakmip1 ko mice compared to wt controls
Exp Paradigm: Protein expression levels measured in postnatal neocortex synaptosomal membranes of jakmip1 ko mice and wt controls
Description: Comparison of the distribution of psd95 mrna in the jakmip1 ko versus wt mice revealed a reduction of psd95 mrna in the monosome and polyribosome fractions from jakmip1 ko mice
Exp Paradigm: Polysome, monosome and mrnp fractions analysed
Description: Pabpc1 and ddx5 proteins showed a statistically significant shift from polyribosome fractions to monosome and mrnp fractions in jakmip1 ko mice compared to controls; jakmip1 contributes to the association of pabpc1 and ddx5 with polyribosomes; jakmip1 peak expression in mouse neocortical development is at p8-p14
Exp Paradigm: Proteins were quantified by western blot in ribosomal fractions
Description: Glun2a (grin2a), glun2b (grin2b), shank2, and shank3a, all members of an nmdar scaffolding complex, were reduced in striatal synapses of jakmip1 ko mice compared to controls during postnatal development, but not adulthood; glun2a, shank2, and shank3a, but not glun2b, were also reduced in synaptosomal membranes from postnatal neocortex of jakmip1 ko mice compared to controls, consistent with regional differences
Exp Paradigm: Western blot; quantification of intensity
Description: Jakmip1 knockout reduces translation; jakmip1 regulates neuronal translation
Exp Paradigm: Fluorescent non-canonical amino acid tagging (funcat); nascent protein synthesis defined as the mean signal intensity (total pixel intensity/area measured); significance across three trials estimated using mixed effects regression with a fixed effect covariate for imaging date and a random intercept for litter
Description: Ddx5, clasp2, pabpc1 and camk2g confirmed jakmip1 binding partners; jakmip1 binds an evolutionarily conserved protein interactome related to neural translation during postnatal cortical development
Exp Paradigm: Both jakmip1 and the binding partners were immunoprecipitated individually to confirm binding
