Brinp1-deficient mice were shown to exhibit an increased density of parvalbumin-expressing interneurons, reduced social interaction, increased locomotor activity, and impairments in memory using two distinct knockout mouse models (Kobayashi et al., 2014; Berkowicz et al., 2016).
Molecular Function
Inhibits cell proliferation by negative regulation of the G1/S transition.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Absence of BRINP1 in mice causes increase of hippocampal neurogenesis and behavioral alterations relevant to human psychiatric disorders.
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Brinp1 knock-out (Brinp1/) mice were generated by Cre-recombinase-mediated removal of the third exon of Brinp1; a targeting vector was constructed to alter the Brinp1 locus in mouse embryonic stem (ES) cells by homologous recombination; Cre-recombinase-mediated deletion of exon 3 was designed to generate a frame shift, resulting in a stop codon in the fourth exon of Brinp1; A correctly targeted clone was injected into BALB/c blastocysts to generate chimeric mice, which were crossed to C57BL/6 Cre deleter transgenic mice Tg(CMV-cre)1Cgn to remove exon 3 and the neomycin cassette from the targeted allele; The Cre transgenic strain induces deletion of loxP-flanked genes in all tissues, including germ cells; The cre gene in this strain is under the transcriptional control of a human cytomegalovirus minimal promoter and is likely to be expressed before implantation during early embryogenesis; It also appears that the cre gene is X-linked since transgene transmission through males is restricted to female offspring;.
Allele Type: Targeted (Knock Out)
Strain of Origin: BALB/c
Genetic Background: BALB/c x C57BL/6
ES Cell Line: Bruce 4 C57BL/6- derived embryonic stem (ES) cells
Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Brinp1 knock-out (Brinp1/) mice were generated by Cre-recombinase-mediated removal of the third exon of Brinp1; a targeting vector was constructed to alter the Brinp1 locus in mouse embryonic stem (ES) cells by homologous recombination; Cre-recombinase-mediated deletion of exon 3 was designed to generate a frame shift, resulting in a stop codon in the fourth exon of Brinp1; A correctly targeted clone was injected into BALB/c blastocysts to generate chimeric mice, which were crossed to C57BL/6 Cre deleter transgenic mice Tg(CMV-cre)1Cgn to remove exon 3 and the neomycin cassette from the targeted allele;.
Allele Type: Targeted (Knock Out)
Strain of Origin: BALB/c
Genetic Background: BALB/c x C57BL/6
ES Cell Line: Bruce 4 C57BL/6- derived embryonic stem (ES) cells
Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Mice harboring a targeted mutation where exon8 was replaced by a PGK-neo cassette from pKJ2.
Allele Type: Targeted (Knock Out)
Strain of Origin: Genetic Background: C57BL/6J
ES Cell Line: Mutant ES Cell Line: TT2 ES cells
Model Source: Kobayashi et al, 2014 (PMID 24528488)
Description: Brinp1 homozygous null mice exhibited hyperactivity compared to wildtype controls; brinp1 homozygous null mice travelled 50 % further, spent less time resting and showed a consistent increase in velocity compared to wt;
Exp Paradigm: Novel cage test; hyperactivity of mice was revealed by testing animals in the locomotor cell over a period of 30 min;
Description: Brinp1 homozygous null mice brains showed an increase in parvalbumin positive interneuron cellularity in layers iv and vi of the neocortex and ca1 region of the hippocampus compared to wildtype control;
Exp Paradigm: Pv
Description: Amount of time the brinp1 homozygous null mice spent digging compared to wild type was decreased
Exp Paradigm: Observation of repetitive behavior;
Description: Brinp1 homozygous null mice showed an increase in stereotypic episodes (repeat motion within a small area)
Exp Paradigm: Observation of repetitive behavior;
Description: Brinp1homozygous null mice showed increased vertical acitivity compared to wildtype controls
Exp Paradigm: Three-chamber social approach test; home cage behavior;-three-chamber social approach test
Description: Brinp1homozygous null mice spent significantly less time interacting with the stranger mouse, showing no difference in interaction time with the empty cage compared to wildtype controls
Exp Paradigm: Three-chamber social approach test;
Description: Brinp1 homozygous null mice showed significantly shorter call durations; this reduced call length reflected changes to the distribution of call types; brinp1 homozygous null mice emitted a higher percentage of short calls and lower percentage of complex or composite longer calls ; compared to wt, brinp1 homozygous null mice showed a trend towards reduced number of calls, a longer latency to call and longer latency to investigate the cotton bud, but these parameters did not reach the 95 % confidence level; also no change in call amplitude was evident, although a trend of increased peak frequency of calls was observed;
Exp Paradigm: Communication was investigated by analysing the ultrasonic vocalisation (usv) calls of male mice presented with pheromones from estrus or proestrous female mice;
Description: Brinp1 homozygous null mice have impaired postnatal growth compared to wildtype controls; these mice exhibited a significant delay in weight gain from age of first weighing (week 3) until adulthood in both male and females; despite a 10 % reduction in adult body weight, brinp1 homozygous null mice had normal body length and normal brain size;
Exp Paradigm: Body weight measurement;
Description: Post-partum survival of progeny of brinp1/ brinp1/ breeders was significantly reduced; brinp1/ mice born from heterozygous breeders were also not observed at the expected mendelian frequency; only 10 out of 75 (13 %) of surviving pups were brinp1/, indicating that half of the brinp1/ mice died in utero or did not survive to weaning; analysis of 18 full-term embryos showed that brinp1/ fetuses were present at expected frequencies (6 out of 18, 33 %). indicating brinp1/ mice have impaired postnatal viability;
Exp Paradigm: Survival analysis;
Description: Little to no milk was present in the stomach of the dead brinp1 hm null animals, indicating lack of adequate nutrition as a likely cause of death
Exp Paradigm: Developmental milestone measurements;
Description: Brinp1homozygous null mice spent proportionally more time in the centre of the locomotor cell;
Exp Paradigm: Three-chamber social approach test;
Description: Male brinp1homozygous null mice spent significantly less time in a closed arm; the number of entries into each arm of the elevated plus maze was unaffected;
Exp Paradigm: Mice were allowed to freely explore an elevated plus maze for 5 min;
Description: Brinp1 homozygous null mice showed no impairment in longterm memory compared to wildtype controls; possibly due to their hyperactivity, male knock-out mice showed faster time, as well as a shorter swim distances required to find the platform compared to wt on day 1 of the experiment
Exp Paradigm: Morris water maze test:
Description: With a 2 hr interval between trials, brinp1 homozygous null mice did not show the typical increase in time spent exploring a novel arm compared to wildtype controls, indicating impaired short-term memory
Exp Paradigm: Y-maze test;
Description: Mothers lacking brinp1 are deficient in postnatal care of their offspring, resulting in neonatal death;
Exp Paradigm: General observations;
Description: Compared to brinp1 wildtype controls brinp1 homozygous null mutants did not express brinp1 protein the mouse brain
Exp Paradigm: Immunohistochemistry; western blot;-immunohistochemistry
Description: Compared to brinp1 wildtype controls brinp1 homozygous null mutants did not express brinp1 protein the mouse brain
Exp Paradigm: Immunohistochemistry; western blot;- western blot
Description: Brinp1 heterozygous females showed delayed weight gain close to that of brinp1 homozygous mice, whereas heterozygous male mice were smaller as juveniles, but their weight recovered close to wt
Exp Paradigm: Body weight measurement;
Description: Litter survival from brinp1 het het breeders was reduced (average of four mice surviving per litter) compared to wt controls;
Exp Paradigm: Survival analysis;
Description: Little to no milk was present in the stomach of the dead brinp1 ht null animals, indicating lack of adequate nutrition as a likely cause of death
Exp Paradigm: Developmental milestone measurements;
Description: Mothers lacking brinp1 are deficient in postnatal care of their offspring, resulting in neonatal death;
Exp Paradigm: General observations;
Description: Compared to brinp1 wildtype controls brinp1 heterozygous null mutants showed reduced expression of brinp1 protein the mouse brain
Exp Paradigm: Immunohistochemistry; western blot;- western blot
Description: The late embryonic brain in brinp1 homozygous null mice (e18.5) showed a 2-fold increase in both astn1 and astn2 mrna compared to wildtype controls
Exp Paradigm: Quantitative pcr (qrt-pcr);
Description: At 6 weeks of age, brinp1 homozygous null mice showed a 3-fold increase in astn1 mrna and a 2-fold increase in astn2 mrna in the hippocampus
Exp Paradigm: Quantitative pcr (qrt-pcr);
Description: Compared to brinp1 wildtype controls brinp1 heterozygous null mutants showed reduced expression of brinp1 protein the mouse brain
Exp Paradigm: Immunohistochemistry; western blot;-immunohistochemistry
Description: Mutants show a decrease in parvalbumin but no change in calretinin postive gabaergic interneurons compared to controls in the medial prefrontal cortex. mutants show a decrease in the parvalbumin and gad67 double positive neurons compared to controls in the medial prefrontal cortex. mutants show a decrease in somatostatin positive neurons in the medial prefrontal cortex compared to controls. mutants show a decrease in somatostatin and gad67 double positive neurons in the medial prefrontal cortex compared to controls.
Exp Paradigm: Pv, gaba, gad67, sst
