Missense variants at conserved residues of the CTNND2 gene were found to be significantly more frequent in autism cases than in controls (P=0.04 vs. 1000 Genomes Project; P=7.8E-04 vs. Exome Variant Server); several of these missense variants exhibited loss-of-function effects by functional analysis in zebrafish embryos and cultured hippocampal neurons (Turner et al., 2015).
Molecular Function
This gene encodes an adhesive junction associated protein of the armadillo/beta-catenin superfamily and is implicated in brain and eye development and cancer formation.
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
A targeted mutation was generated in exon 9 of the Ctnnd2 gene, a GFP reporter and a PGK-hygro-PA selection cassette containing a stop codon, was inserted in the exon. Exon 9 has the armadillo repeats that are needed for protein localization.
Allele Type: Targeted(knockout/reporter)
Strain of Origin: 129SvJ
Genetic Background: C57BL/6NTac:129/SvJ
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Delta-catenin G34S mice (RRID:MMRRC_050621-UCD) were generated by Dr. Jyothi Arikkath at UNMC Mouse Genome Engineering Core using the CRISPR-Cas9 technique. Human and mouse delta-catenin proteins both contain glycine 34, according to amino acid sequence analysis. The CRISPR-Cas9 reagents were injected into zygotes derived from C57BL6/J mice. The sgRNA is in antisense orientation, and it cleaved immediately downstream of the codon GGC (glycine 34) of the delta-catenin gene, yielding a double-strand break. Non-homologous end joining was used to repair the breaks, which resulted in the G34S mutation being inserted into the delta-catenin gene in vivo. The founder mouse was crossed with WT C57BL6/J mice to create heterozygous delta-catenin G34S mice, which were subsequently used to make homozygous G34S animals.
Allele Type: ASD mutation
Strain of Origin: C57BL/6J
Genetic Background: C57BL/6J
ES Cell Line: Not Specified
Mutant ES Cell Line: Model Source: University of Nebraska Medical Center (UNMC) Mouse Genome Engineering Core
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Delta-catenin knockout mouse was developed in collaboration with Cyagen Biosciences Inc. utilizing the CRISPR-Cas9 technique. Cas9 mRNA and two single guide RNAs (sgRNAs) were microinjected into the C57BL6/J zygotes, where sgRNAs directed Cas9 endonuclease to cleave within intron 1 and intron 2 of the mouse delta-catenin gene, yielding a double-strand break, which removed the exon 2 that contained the ATG initiation codon. Such breaks were repaired by non-homologous end joining, resulting in disruption of the delta-catenin gene expression in vivo. The founder mouse was crossed with WT C57BL6/J mice to create heterozygous delta-catenin knockout mice, which were subsequently used to make homozygous knockout animals in the C57BL6/J background. The animals used in the proposed research have been fully crossed to C57BL6/J mice for more than eight generations.
Allele Type: Knockout
Strain of Origin: C57BL/6J
Genetic Background: C57BL/6J
ES Cell Line: Not Specified
Mutant ES Cell Line: Model Source: PMID 36711484
Description: Delta catenin null mice show reduced motor coordination and balance in the accelerating rotarod test as they show a shorter latency of falling off than wild type controls
Exp Paradigm: NA
Description: Instead of long-term depression, a potentiaion is generated in the hippocampal slices of delta catenin null mice, wherease the same stimulation protocol causes a depression in wild type slices
Exp Paradigm: NA
Description: Paired pulse facilitation ratio is significantly reduced in delta catenin null mice, in several inter-stimulus intervals (ipis) in the range of 50-200ms
Exp Paradigm: NA
Description: There is enhanced ltp (abnormal) generated in response to high frequency stimulation of the hippocampal synapses in delta catenin null brain slices, compared to wild type slices
Exp Paradigm: NA
Description: There is decreased ltp compared to wild type, when a low frequency protocol is used to generate ltp in delta catenin null hippocampal slices
Exp Paradigm: NA
Cued or contextual fear conditioning: memory of context1
Decreased
Description: Delta catenin null mice have reduced memory of acoustic cue in the fear conditioning test as they freeze less following the cue tone.
Exp Paradigm: NA
Description: Delta catenin null mice have significantly reduced spatial memory as they do not spend increased time in the quadrant that contained the hidden platform, unlike the wt controls, in the probe trial conducted following the training phase
Exp Paradigm: NA
Description: Delta catenin null mice are significantly impaired in spatial learning in the training trials of the hidden platform test in mwm
Exp Paradigm: NA
Cued or contextual fear conditioning: memory of cue1
Decreased
Description: Delta catenin null mice have reduced memory of the context they received a shock in as they freeze less when place in the same context the day after the training phase.
Exp Paradigm: NA
Description: Mutant male mice exhibited significantly decreased GluA2 levels in the cortex compared to wildtype controls, while no significant differences were found between wildtype and mutant female mice. Female and male mutant mice exhibited no significant difference in total GluA1 and synaptic GluA1 levels in the cortex, and no change in GluA1 and GluA2 levels in the hippocampus, compared to wildtype controls.
Exp Paradigm: Cortex, hippocampus
Description: Mutant female and male mice displayed no significant difference in total interaction time between stranger 1 and the novel object, while wildtype female and male mice interacted significantly longer with stranger 1 than the novel object during the sociability test, an indication of normal sociability. Additionally, social interaction time with stranger in mutant female and male mice was significantly less than wildtype mice.
Exp Paradigm: Stranger mouse in chamber 1, non-social object in chamber 2
Description: Mutant female and male mice displayed no significant difference in reciprocal sniffing time between stranger 1 and stranger 2, while wildtype mice engaged with stranger 2 for longer than they did with stranger 1, demonstrating normal social novelty preference. Additionally, mutant female and male mice displayed lower social interaction with stranger 2 compared to wildtype controls.
Exp Paradigm: Familiar mouse in chamber 1, stranger mouse in chamber 2
Description: Female and male mutant mice exhibited a significant decrease in synaptic delta-catenin in the cortex compared to wildtype controls. In the hippocampus, female and male mutant mice exhibited no change in synaptic delta-catenin levels.
Exp Paradigm: Cortex, hippocampus
Description: Mutant male mice exhibited significantly decreased levels of total delta-catenin in the cortex compared to wildtype controls, while no significant differences were found between wildtype and mutant female mice.
Exp Paradigm: Cortex
Description: Mutant female and male mice exhibited a significant decrease in synaptic GluA2 levels, and no difference in synaptic GluA1 levels, in the cortex compared to wildtype controls. Additionally, mutant female and male mice exhibited no difference in synaptic GluA1 and GluA2 levels in the hippocampus compared to wildtype controls.
Exp Paradigm: Cortex, hippocampus
Description: In the social novelty phase, wildtype controls exhibited a preference for exploring the new mouse (S2) over a familiar (S1) one, whereas Ctnnd2 mutant mice failed to exhibit a preference between the two subjects. Compared to wildtype animals, social interaction with stranger 2 was significantly lower in both female and male mutant mice.
Exp Paradigm: Familiar mouse in chamber 1, stranger mouse in chamber 2
Description: Ctnnd2 mutant male and female mice displayed decreased social ability in the social approach phase, exhibiting similar total interaction times with the stranger mouse (S1) compared to an the empty cup. In relation to wildtype controls, the amount of time spent interacting with a stranger mouse was significantly decreased.
Exp Paradigm: Stranger mouse in chamber 1, non-social object in chamber 2
