Evolution of Molecular Function in Mammalian Neurons

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Doctor of Philosophy (PhD)
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Cell Biology
Molecular Biology
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A common question in neuroscience is what forms the neurological basis of the variety of behaviors in mammals. While many studies have compared mammalian anatomy and evolution, few have investigated the physiologic functions of individual neurons in a comparative manner. Neurons’ ability to modify their features in response to stimuli, known as synaptic plasticity, is fundamental for learning and memory. A key feature of synaptic plasticity involves delivering mRNA to distinct domains where they are locally translated. Regulatory coordination of these events is critical for synaptogenesis and synaptic plasticity as defects in these processes can lead to neurological diseases. In this work, we combine computational and experimental biology to investigate subcellular localization of mRNAs in dendrites of mouse and rat neurons. Differential subcellular localization of specific gene products may highlight differential synaptic function and allow the uncovering of evolutionary conserved as well as divergent molecular functions in neurons. First, we performed a comparative analysis of the dendritic transcriptome in mouse and rat via microarrays. We found that their dendritic transcriptome are significantly more divergent than other homologous tissues and that these evolutionarily changes could be associated with transposon activity. Second, we comprehensively determined subcellular expression patterns for neuronal genes in mice and rats via a systematic in situ survey on a curated list of dendritic mRNA from our previous microarray study. This survey highlighted that dendritic localization of specific transcripts occurs in a species-specific fashion. We uncovered species-specific cis and trans-elements with possible implications in transcript localization and gene expression regulation in neurons. The interactions between these elements might play a major role in the proper development and evolution of complex nervous systems. Our data will be publically available in a database (http://kim.bio.upenn.edu/insitu/public/), which could guide future investigations. Finally, we investigated single cell variability by combining microarrays, RNAseq and in situ experiments. Our preliminary results underlined the extent of this variability and its contributions in establishing cell’s unique identity. In conclusion, our study suggests the existence of species-specific mRNA localization mechanisms and supports the idea that evolution of phenotypes might be linked to the evolution of subcellular localization of transcripts.

Junhyong Kim
Jim Eberwine
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