| First Author | Wickham RJ | Year | 2019 |
| Journal | Hum Mol Genet | Volume | 28 |
| Issue | 17 | Pages | 2965-2975 |
| PubMed ID | 31131404 | Mgi Jnum | J:294409 |
| Mgi Id | MGI:6456307 | Doi | 10.1093/hmg/ddz115 |
| Citation | Wickham RJ, et al. (2019) Learning impairments and molecular changes in the brain caused by beta-catenin loss. Hum Mol Genet 28(17):2965-2975 |
| abstractText | Intellectual disability (ID), defined as IQ<70, occurs in 2.5% of individuals. Elucidating the underlying molecular mechanisms is essential for developing therapeutic strategies. Several of the identified genes that link to ID in humans are predicted to cause malfunction of beta-catenin pathways, including mutations in CTNNB1 (beta-catenin) itself. To identify pathological changes caused by beta-catenin loss in the brain, we have generated a new beta-catenin conditional knockout mouse (beta-cat cKO) with targeted depletion of beta-catenin in forebrain neurons during the period of major synaptogenesis, a critical window for brain development and function. Compared with control littermates, beta-cat cKO mice display severe cognitive impairments. We tested for changes in two beta-catenin pathways essential for normal brain function, cadherin-based synaptic adhesion complexes and canonical Wnt (Wingless-related integration site) signal transduction. Relative to control littermates, beta-cat cKOs exhibit reduced levels of key synaptic adhesion and scaffold binding partners of beta-catenin, including N-cadherin, alpha-N-catenin, p120ctn and S-SCAM/Magi2. Unexpectedly, the expression levels of several canonical Wnt target genes were not altered in beta-cat cKOs. This lack of change led us to find that beta-catenin loss leads to upregulation of gamma-catenin (plakoglobin), a partial functional homolog, whose neural-specific role is poorly defined. We show that gamma-catenin interacts with several beta-catenin binding partners in neurons but is not able to fully substitute for beta-catenin loss, likely due to differences in the N-and C-termini between the catenins. Our findings identify severe learning impairments, upregulation of gamma-catenin and reductions in synaptic adhesion and scaffold proteins as major consequences of beta-catenin loss. |
