Kctd13-deficient mice display short-term memory impairment and sex-dependent genetic interactions

Abstract

The 16p11.2 BP4-BP5 deletion and duplication syndromes are associated with a complex spectrum of neurodevelopmental phenotypes that includes developmental delay and autism spectrum disorder, with a reciprocal effect on head circumference, brain structure and body mass index. Mouse models of the 16p11.2 copy number variant have recapitulated some of the patient phenotypes, while studies in f lies and zebrafish have uncovered several candidate contributory genes within the region, as well as complex genetic interactions. We evaluated one of these loci, KCTD13, by modeling haploinsufficiency and complete knockout in mice. In contrast to the zebrafish model, and in agreement with recent data, we found normal brain structure in heterozygous and homozygous mutants. However, recapitulating previously observed genetic interactions, we discovered sex-specific brain volumetric alterations in double heterozygous Kctd13xMvp and Kctd13xLat mice. Behavioral testing revealed a significant deficit in novel object recognition, novel location recognition and social transmission of food preference in Kctd13 mutants. These phenotypes were concomitant with a reduction in density of mature spines in the hippocampus, but potentially independent of RhoA abundance, which was unperturbed postnatally in our mutants. Furthermore, transcriptome analyses from cortex and hippocampus highlighted the dysregulation of pathways important in neurodevelopment, the most significant of which was synaptic formation. Together, these data suggest that KCTD13 contributes to the neurocognitive aspects of patients with the BP4-BP5 deletion, likely through genetic interactions with other loci.

KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders

“…However, recent studies reported no robust abnormalities in brain structure of mice with genetic ablation of Kctd13, and instead observed sex-specific differences in brain volume of double heterozygous mice lacking one copy of Kctd13 and one copy of either Lat or Mvp, also located in 16p11.2. 75 These results suggest that altered dosage of Kctd13, and Mvp or Lat may have epistatic effects on brain size.…”

“…Other studies demonstrate that in mouse models, Kctd13 epistatically affects anatomical phenotypes in combination with Mvp (major vault protein) or Lat (linker for activation of T cells) , genes, which are also located in 16p11.2 loci. However, recent studies reported no robust abnormalities in brain structure of mice with genetic ablation of Kctd13 , and instead observed sex‐specific differences in brain volume of double heterozygous mice lacking one copy of Kctd13 and one copy of either Lat or Mvp , also located in 16p11.2 . These results suggest that altered dosage of Kctd13 , and Mvp or Lat may have epistatic effects on brain size.…”

“…75 However, RNA-seq analyses of gene expression profiles from the cortex and hippocampus of Kctd13 -deficient (exon 2-deleted) mice revealed altered signaling pathways critical for neurodevelopment, including synaptic formation, and both knockout mouse lines exhibited reduced spine density in the hippocampus. 11,75 Thus, further studies are required to understand the mechanistic complexities by which Kctd13 copy number modulates brain development beyond RhoA signaling. It would also be of great interest to investigate how multiple genes in 16p11.2 loci interplay to regulate brain development and contribute to neurodevelopmental abnormalities and psychiatric disorders such as schizophrenia and autism.…”

Leveraging biobank-scale rare and common variant analyses to identify ASPHD1 as the main driver of reproductive traits in the 16p11.2 locus

“…The mass-univariate statistical analysis of whole-brain volume maps was performed in 146 postpubertal individuals as described [34]. Mouse MRI was performed as detailed in [35].…”

Integrated Transcriptome Analyses Revealed Key Target Genes in Mouse Models of Autism

“…Interestingly, a significant number of ASD genes have been shown to play important roles in gene expression regulation, including transcriptional factors, chromatin remodeling factors and other types of epigenetic regulators, such as CHD8, FMR1, MECP2, and so on [Alonso-Gonzalez, Rodriguez-Fontenla, & Carracedo, 2018;De Rubeis et al, 2014]. Accordingly, numerous loss of function animal models were generated, especially the mouse models, to recapitulate the disease phenotypes and to explore the underlying molecular mechanisms [Araujo et al, 2017;Arbogast et al, 2018;Caubit et al, 2016;Celen et al, 2017;Cheng et al, 2018;Gabel et al, 2015;Harrington et al, 2016;Huang et al, 2018;Jung et al, 2018;Kong et al, 2014;McGill et al, 2018;Prilutsky et al, 2015;Provenzano et al, 2016;Raman et al, 2018;Scandaglia et al, 2017;Sgado et al, 2013;Suetterlin et al, 2018;Zhao, Goffin, Johnson, & Zhou, 2013]. With these models, RNA-Seq or microarray experiments have been performed in various brain regions to identify the downstream targets of the corresponding ASD genes.…”