Identifying novel convergent roles of neuronal β-catenin and APC in modulating mRNA translation, plasticity and learning

Author:

Jacob Michele1,Alexander Jonathan1,Jin Shan-Xue,Feig Larry2

Affiliation:

1. Tufts University

2. Tufts University School of Medicine

Abstract

Abstract β-catenin (β-cat) malfunction is a significant risk factor for intellectual disability (ID). However, the underlying mechanisms are poorly defined. We identify a novel role for truncated β-cat that significantly impacts learning. N-terminally truncated β-cat is generated endogenously in neurons by high activity stimulating calcium-dependent calpain cleavage of full-length β-cat. Its role is undefined. We overexpressed N-terminally truncated β-cat in mouse glutamatergic neurons, and show drastic decreases in learning, plasticity and glutamatergic synaptic proteins, and altered translation. Truncated β-cat associates with the pre-initiation complex. Its overexpression perturbs activity-dependent increases in translation near synapses and alters APC (adenomatous polyposis coli protein) association with and translation of its target mRNAs. Several mRNAs in APC’s interactome link to ID. As further evidence of APC malfunction induced by excessive truncated β-cat, genetically depleting APC from β-cat overexpressor neurons prevents the aberrant glutamatergic synaptic protein levels. We identify new convergent roles for APC and truncated β-cat as in vivo effectors of translation and cognitive function.

Publisher

Research Square Platform LLC

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