Collaborative Research: Evolution of neurons through the lens of mRNA regulation.

The origin of neurons in the animal kingdom has remained as a standing question in the field of neuroscience and evolutionary biology. In this project, a collaborative team with expertise in molecular biology, bioinformatics, evolutionary biology, and neurobiology will investigate the molecular mechanisms that regulate neuronal function in distant animal species. More specifically, this project explores whether mechanisms that regulate the generation of proteins from specific mRNAs in response to neuronal activity are present in ctenophores, ocean invertebrates that branched off from other animals more than 800 million years ago, as they are in most other animals including insects and mammals. Answering this question, along with the identification of genes regulated by these mechanisms, will reveal the degree of conservation among the most distant known neuronal systems. In addition, results from this grant will generate important insight into the understanding whether neurons of all animals share a common ancestor, or whether neurons evolved independently in different animal lineages. Development of scientists in training at the undergraduate, doctoral, and post-doctoral levels is supported by this project at both the University of Massachusetts Boston and at the University of Florida. Outreach activities to train high school students associated with the University of Florida's Center for Precollegiate Education in bioinformatics and molecular biology will extend the benefits of this project to future generations of researchers from the broader community. This project advances NSF’s priorities in Biotechnology. Recent evolutionary studies place Ctenophora, rather than the neuron-less Porifera, as the earliest diverging animal lineage. This has led to a fascinating debate regarding whether neurons were present in the last common ancestor of all animals or if neurons of ctenophores arose independently from those of cnidarians and bilaterians. Whereas this question has been approached using genomic inventories, this project provides a new perspective by uncovering the role of Cytoplasmic Polyadenylation Element-Binding proteins (CPEBs) in ctenophore neurons. CPEBs are animal-specific regulators of mRNA that modulate localized translation and synaptic plasticity in bilaterians but are yet to be studied in neurons outside Bilateria. Preliminary data for this project show that a CPEB2 ortholog is preferentially expressed in neurons of the ctenophore Mnemiopsis leidyi, and that a CPEB1 ortholog in this species directs cytoplasmic polyadenylation events conserved in bilaterians. The hypothesis that CPEB2 regulates translation in the cytoplasm of ctenophore neurons will be tested by the following: 1) determining the distribution of CPEB2 in the Mnemiopsis nervous system; 2) identifying the genes post-transcriptionally regulated by CPEB2 in Mnemiopsis neurons; 3) identifying protein partners that assist in CPEB2-mediated regulation of target mRNAs in Mnemiopsis; and 4) mapping the neuronal circuitry in ctenophore tentacles and quantifying transcriptional, post-transcriptional, and translational changes in response to sensory stimuli that correlate with CPEB2 binding. These experiments will address fundamental questions regarding the molecular mechanisms of ctenophore neurons and shed light on the evolutionary history of mRNA regulation in animal synapses. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria. NSF Award ID: 2445895 | Program: 01002627DB NSF RESEARCH & RELATED ACTIVIT | Principal Investigator: Joseph Ryan | Institution: University of Florida, GAINESVILLE, FL | Award Amount: $360,000 View on NSF Award Search: https://www.nsf.gov/awardsearch/show-award/?AWD_ID=2445895 View on Research.gov: https://www.research.gov/awardapi-service/v1/awards/2445895.html