Phenotypes Associated with This Genotype

Genotype
MGI:2664086

• Allelic Composition: Mbd1^tm1Fhg/Mbd1^tm1Fhg
• Genetic Background: 129S4/SvJae-Mbd1^tm1Fhg

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

nervous system

abnormal neuron differentiation ( J:83613 )

• in culture, adult neural stem cells (ANCs) isolated from homozygous mutant brains differentiate into 41% fewer type III beta-tubulin-positive (TuJI⁺) neurons than wild-type cells, indicating reduced neuronal differentiation; however, no significant difference in the % of differentiated astrocytes (GFAP⁺) is observed

• in vivo, adult homozygotes show a 54.9% decrease in the number of BrdUrd⁺ cells and a 42.9% decrease in the percentage of new neurons in the dentate gyrus indicating an overall 74.3% decrease in the number of new neurons relative to wild-type littermates

• in contrast, the percentages of new astrocytes (GFAP⁺ and BrdUrd⁺) and cells with unknown phenotype (BrdUrd⁺, NeuN^-, and GFAP^-) are increased in the dentate gyrus of mutant mice relative to wild-type controls

abnormal hippocampus development ( J:83613 )

• adult homozygotes display a significantly reduction in hippocampal neurogenesis, with little change in astrocytogenesis relative to wild-type littermates

decreased brain weight ( J:83613 )

• adult mutant forebrains weigh 15.2% less than those of wild-type littermates

• however, no significant difference in body weight between adult wild-type and mutant mice is observed

abnormal dentate gyrus morphology ( J:83613 )

• adult homozygotes show an 8.1% reduction in the cell density of the dentate gyrus relative to wild-type littermates

abnormal long-term potentiation ( J:83613 )

• homozygotes display a severe reduction of LTP in the detate gyrus of the hippocampus relative to wild-type littermates

• in contrast, LTP in the CA1 region of the hippocampus remains relatively unaffected

behavior/neurological

behavior/neurological phenotype ( J:83613 )

N • adult homozygotes are healthy and display no significant deficits in motor coordination or locomotor activity, as determined in the rotarod test and open field test

abnormal spatial learning ( J:83613 )

• in the Morris water maze test, adult homozygotes require a significantly longer time than wild-type mice to locate a hidden platform, even after 9 days of training

• upon removal of the platform, homozygotes spend more time in the start (opposite) quadrant searching for the platform, whereas wild-type mice spend more time in the target quadrant

cellular

aneuploidy ( J:83613 )

• analysis of prometaphase/metaphase spreads indicated that mutant ANCs show a significantly higher aneuploidy than wild-type ANCs (46% vs 21.3%, respectively)

• unlike most wild-type aneuploid ANCs which typically lose chromosomes, the majority of mutant aneuploid ANCs (67.6%) are shown to gain chromosomes

• 9 of 16 mutant aneuploid ANCs cells analyzed by SKY were shown to gain chromosome 10 whereas none of the 11 aneuploid wild-type cells gained chromosome 10

abnormal neuron differentiation ( J:83613 )

• in culture, adult neural stem cells (ANCs) isolated from homozygous mutant brains differentiate into 41% fewer type III beta-tubulin-positive (TuJI⁺) neurons than wild-type cells, indicating reduced neuronal differentiation; however, no significant difference in the % of differentiated astrocytes (GFAP⁺) is observed

• in vivo, adult homozygotes show a 54.9% decrease in the number of BrdUrd⁺ cells and a 42.9% decrease in the percentage of new neurons in the dentate gyrus indicating an overall 74.3% decrease in the number of new neurons relative to wild-type littermates

• in contrast, the percentages of new astrocytes (GFAP⁺ and BrdUrd⁺) and cells with unknown phenotype (BrdUrd⁺, NeuN^-, and GFAP^-) are increased in the dentate gyrus of mutant mice relative to wild-type controls

chromosomal instability ( J:83613 )

• mutant ANCs display a small but significant increase of endogenous viral (IAP) expression at both the mRNA (2.8-fold) and protein (5.4-fold) level relative to wild-type ANCs. suggesting increased genomic instability

• treatment with trichostatin A (TSA), a histone deacetylase inhibitor, caused a significantly higher increase of IAP expression in mutant ANCs (3-fold) than in wild-type cells (0.37-fold)

• however, no significant differences in the methylation status of IAP-LTR or in the global DNA methylation level were observed between mutant and wild-type ANCs

chromosome breakage ( J:83613 )

• 3 of 29 mutant aneuploid ANCs, but none of 30 wild-type prometaphase/metaphase cells, analyzed by SKY were shown to have gained a fragment of chromosome 2, suggesting a possible chromosomal breakage

• however, no chromosomal translocation was detected among the cells analyzed