The broad objective of this proposal is to delineate mechanisms of mRNA translation in mammalian neurons and especially dendrites that modify synaptic efficacy. CPEB, a sequence-specific mRNA binding protein that promotes cytoplasmic polyadenylation- induced translation, is present at synapto-dendrites of mammalian neurons. CPEB knockout mice display defects in synaptic plasticity and learning and memory, indicating the importance of the cytoplasmic polyadenylation machinery in complex brain function. CPEB nucleates a set of factors on mRNA to promote polyadenylation including the non- canonical poly(A) polymerase Gld2, the deadenylating enzyme PARN, the eIF4E-binding protein neuroguidin (Ngd), the scaffold protein symplekin, and others. These proteins reside in a complex in dendrites of mammalian neurons where they modulate the polyadenylation and translation of several mRNAs. Two of these factors, Gld2 and Ngd, regulate synaptic plasticity in hippocampal neurons but do so in opposite directions;Gld2 depletion induces a deficit in long-term potentiation (LTP) while Ngd depletion enhances it. Moreover, Gld2 depletion reduces translation in dendrites while Ngd depletion stimulates it. These data indicate that the interplay among CPEB, Gld2, and Ngd form a coherent molecular foundation of translation control in dendrites that in turn modulates synaptic efficacy. The goals of the first specific aim are to identify deadenylating enzymes that are likely to modify poly(A) length and changes in translation as well as to assess whether they influence synaptic function.
Aim 2 is to investigate the full panoply of mRNAs that are bound by CPEB in the brain and determine whether they undergo activity-dependent polyadenylation and translation in dendrites. The goal of aim 3 is to develop and use a new deep sequencing method to identify dendritic mRNAs that undergo cytoplasmic polyadenylation and translation in response to in LTP induction in vitro and learning in vivo. These experiments will enhance our understanding of how local mRNA translation in neurons mediates synapse function, which has important implications for higher brain function and neuropathies such as autism, Alzheimer's Disease, Parkinson's Disease, and others.
Translational control is one process that regulates synaptic plasticity and learning and memory. Consequently, this proposal has important implications for human health particularly as it relates to brain functions such as memory loss, dementia, and organismal aging.
|Ivshina, Maria; Lasko, Paul; Richter, Joel D (2014) Cytoplasmic polyadenylation element binding proteins in development, health, and disease. Annu Rev Cell Dev Biol 30:393-415|
|Udagawa, Tsuyoshi; Farny, Natalie G; Jakovcevski, Mira et al. (2013) Genetic and acute CPEB1 depletion ameliorate fragile X pathophysiology. Nat Med 19:1473-7|