Learning impairments and molecular changes in the brain caused by ß-catenin loss.
Hum Mol Genet
; 28(17): 2965-2975, 2019 09 01.
Article
in En
| MEDLINE
| ID: mdl-31131404
ABSTRACT
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 ß-catenin pathways, including mutations in CTNNB1 (ß-catenin) itself. To identify pathological changes caused by ß-catenin loss in the brain, we have generated a new ß-catenin conditional knockout mouse (ß-cat cKO) with targeted depletion of ß-catenin in forebrain neurons during the period of major synaptogenesis, a critical window for brain development and function. Compared with control littermates, ß-cat cKO mice display severe cognitive impairments. We tested for changes in two ß-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, ß-cat cKOs exhibit reduced levels of key synaptic adhesion and scaffold binding partners of ß-catenin, including N-cadherin, α-N-catenin, p120ctn and S-SCAM/Magi2. Unexpectedly, the expression levels of several canonical Wnt target genes were not altered in ß-cat cKOs. This lack of change led us to find that ß-catenin loss leads to upregulation of γ-catenin (plakoglobin), a partial functional homolog, whose neural-specific role is poorly defined. We show that γ-catenin interacts with several ß-catenin binding partners in neurons but is not able to fully substitute for ß-catenin loss, likely due to differences in the N-and C-termini between the catenins. Our findings identify severe learning impairments, upregulation of γ-catenin and reductions in synaptic adhesion and scaffold proteins as major consequences of ß-catenin loss.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Brain
/
Disease Susceptibility
/
Beta Catenin
/
Learning
Type of study:
Diagnostic_studies
/
Etiology_studies
/
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Hum Mol Genet
Journal subject:
BIOLOGIA MOLECULAR
/
GENETICA MEDICA
Year:
2019
Document type:
Article
Affiliation country: