The role of adenomatous polyposis coli and beta-catenin proteins in intellectual disabilities and autism
Alexander, Jonathan.
2017
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Abstract: Autism
spectrum disorders and intellectual disabilities are neurodevelopmental co-morbidities
seen in a growing percentage of the population. Large-scale genetic screens of patients
with these disorders have revealed that a large proportion of autism causing genes
center on key central pathways. One such pathway is the Wnt/β-catenin pathway,
with the highest confidence risk gene for ... read moresporadic autism, CHD8, being a regulator of
Wnt target gene expression. However, direct tests are lacking for a role of
β-catenin malfunction, particularly excessive β-catenin signaling, leading
to these disorers. Mutations in adenomatous polyposis coli (APC) and β-catenin,
two critical molecules in the Wnt pathway, have been associated with autism and
intellectual disabilities. β-catenin functions both at the synapse - in adhesion
complexes with the trans-synaptic binding protein N-cadherin, and in the nucleus - as a
transcription factor regulating the expression of Wnt target genes. APC is the major
negative regulator of β-catenin, forming a destruction complex with Axin and
GSK3β that is responsible for targeting β-catenin to the proteasome. APC
also is a major regulator of cytoskeletal dynamics by binding microtubules and guiding
polarity, and an mRNA binding protein that targets mRNAs critical for neuronal
development and function. This dissertation focuses on how mutations in APC and
β-catenin may contribute to the pathophysiology of autism and intellectual
disabilities. We did this using three new mutant mouse models: the APC cKO, β-cat
cOE, and APC/β-cat cKO mice (cKO: conditional knockout, cOE: conditional
overexpression). APC cKO mice display mild cognitive impairments and autistic-like
phenotypes (reduced sociability and increased repetitive behaviors). APC cKO mice show
increased in β-catenin levels, increased Wnt target gene expression, modestly
enhanced LTP, increased spine density, and increased synaptic association of
β-catenin with N-cadherin. Working on the hypothesis that the observed increase in
β-catenin was a major driving force for the cognitive and behavioral phenotypes of
the APC cKO, we examined if overexpression of β-catenin was sufficient to
replicate the phenotypes. β-cat cOE mice show severe cognitive impairments
relative to the APC cKO, with dramatically reduced plasticity (LTP and LTD) and
reductions in the membrane levels of the glutamate receptor subunits GluR1 and NR2A/B.
We show reductions in protein levels of an APC mRNA target, SynCAM1that plays a role in
GluR1 insertion. Interestingly, we see a gel-mobility shift in APC suggesting a
post-translational modification of APC that is unique to the β-cat cOE. As
β-cat cOE mice also display the autistic-like phenotypes we observe in the APC cKO
model, we tested if preventing the increase in β-catenin in the APC cKO, by
conditionally removing the ctnnb1 gene product as well, would ameliorate the behavioral
deficits. APC/β-cat cKO mice demonstrate normal social and repetitive behaviors,
suggesting a role for increased β-catenin in the autistic like phenotypes we
observed in the other models. Interestingly, these mice display cognitive deficits that
are comparable to the APC cKO and an increase in Wnt target gene expression that may be
mediated through an increase in the β-catenin family member, γ-catenin. This
dissertation provides new insights into the roles of APC and β-catenin in
behaviors associated with autism and intellectual disabilities. We demonstrate that
increased β-catenin may contribute to the autism phenotype in mice and that APC
may play new and important functions in regulating plasticity. These new models will
serve as important genetic tools for understanding the pathophysiology underlying ASD
and ID.
Thesis (Ph.D.)--Tufts University, 2017.
Submitted to the Dept. of Neuroscience.
Advisor: Michele Jacob.
Committee: Leon Reijmers, Larry Feig, Jamie Maguire, and Mark Bear.
Keyword: Neurosciences.read less - ID:
- 1831cw832
- Component ID:
- tufts:20648
- To Cite:
- TARC Citation Guide EndNote
