Adenomatous Polyposis Coli (APC) is Essential for Synapse Maturation, Synaptic Plasticity, and Normal Behavior.
Abstract: Autism is a developmental disorder characterized by repetitive, stereotyped behaviors, reduced social interactions, and reduced communication. The pathology of autism is believed to be caused by underlying defects in neuronal connectivity, and synaptic maturation and plasticity. Autism has a strong genetic component, showing associations with many single-gene mutations. Mutations in FMR1... read more, NL3, and APC are all associated with autism in humans. The tumor suppressor APC is negative regulator of the Wnt signaling pathway, and has recognized roles in the organization of microtubules, and guidance of neuronal growth cones. APC's roles in synapse maturation and synaptic plasticity, however, are poorly defined. APC interacts with numerous proteins that regulate synaptic maturation and plasticity, such as FMRP, β-catenin, and PSD-95, suggesting that APC may be central in a novel pathway that directs neuronal connectivity, and synapse differentiation and function--all implicated in autism. In this dissertation, I use two model systems to define the role of APC at neuronal synapses in vivo. Our studies using dominant negative blocking peptides show that APC interactions with the microtubule plus-end binding protein EB1 are essential for coordinating the maturation of both presynaptic and postsynaptic specializations at nicotinic synapses in the embryonic chick parasympathetic ciliary ganglion. Our findings provide the first identification of a protein that is required, in vivo, for targeting nAChRs, neuroligin and neurexin to neuronal synapses To define the role of APC at central synapse, we generated a new transgenic mouse with conditional knock-out of the APC gene in excitatory neurons during synapse differentiation (APC cKO). I have shown that APC is required for proper synaptic maturation, and plasticity, learning and memory formation, and social behaviors. APC cKO mice display autistic-like behaviors , including increased repetitive behaviors, reduced social interactions and reduced bimanual fine motor coordination, as well as cognitive deficits (delayed learning, poor long-term memory), and aberrant plasticity (enhanced LTP and LTD). APC cKO mice also display agenesis of the corpus callosum, a structural feature that is common in autistic individuals and correlates with impaired social cognition and bimanual coordination. I find altered expression levels of key regulators of synaptic plasticity, including NL3 and FMRP, and thereby identify APC as a novel regulator of NL3 and FMRP protein levels in the hippocampus in vivo. FMRP null mutations are the most common cause of autism and intellectual disability in humans, highlighting the importance of identifying molecules that regulate its levels in vivo. Similarly, APC cKO mice exhibit altered levels of two other pathways, Wnt/β-catenin and ERK2, that have been implicated in autism caused by diverse gene mutations. My data define a critical role for APC in directing neuronal maturation and connectivity during development, and regulating synaptic plasticity pathways that are focal to autism. The APC cKO mouse is a useful new model for elucidating molecular causes and potential treatments for autism.
Thesis (Ph.D.)--Tufts University, 2012.
Submitted to the Dept. of Cell, Molecular & Developmental Biology.
Advisor: Michele Jacob.
Committee: Victor Hatini, James Schwob, Peter Juo, and Michael Greenberg.
Keywords: Cellular biology, and Neurosciences.read less