Mammalian behavior spans a fantastic range of function and ability, from complex linguistic processing, to social and sexual behavior, to simple stimulus-response. Traditional explanations of the mechanisms for this diversity include brain size, neuro- anatomy, and functional neuro-anatomy including connectivity patterns. Establishing these neuro-anatomical differences requires evolutionary differences in the genes guiding developmental processes. However, there has been little comparative studies focused on individual neuronal function in a non-developmental context. Previously, we initiated a project to understand what sequence motifs govern sub-cellular localization of mRNA to dendrites in rat neurons. Surprisingly, we found evidence that an evolutionarily novel element may partly govern dendritic localization. Furthermore, this element is abundant in the rat genome but an order of magnitude less abundant in the mouse genome. A micro-dissection and expression array survey of the mouse neurons seem to suggest that there is only 36% overlap between the homologous mRNA found in the mouse dendrites and the rat dendrites. Thus, we hypothesize that the genome-scale molecular physiology of neurons from different tissues and closely related species have broad differences and functional non-coding RNA derived from evolutionarily novel elements plays a role in establishing these differences. If true, this would have important consequences for translating animal neurobiological studies to humans and also suggest that evolutionarily novel elements such as retroviral-derived elements may be important in brain function and dysfunction. We propose to test our hypothesis using comparative single-cell localization assays, single-cell transcriptome assays, whole-transcriptome sequencing, and functional analysis.

Public Health Relevance

In this project, we hypothesize that the genome-scale molecular physiology of neurons from different tissues and closely related species have broad differences and functional non-coding RNA derived from evolutionarily novel elements plays a role in establishing these differences. We propose to test our hypothesis using comparative single-cell localization assays, single-cell transcriptome assays, whole-transcriptome sequencing, and functional analysis. The results of our investigation will have important consequences for translating animal model neurobiological studies to humans diseases and also suggest that viral-derived elements may be important in brain function and neurodegenerative diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH088849-04
Application #
8269573
Study Section
Special Emphasis Panel (ZMH1-ERB-L (05))
Program Officer
Beckel-Mitchener, Andrea C
Project Start
2009-08-18
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2014-04-30
Support Year
4
Fiscal Year
2012
Total Cost
$306,873
Indirect Cost
$108,873
Name
University of Pennsylvania
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Khaladkar, Mugdha; Buckley, Peter T; Lee, Miler T et al. (2013) Subcellular RNA sequencing reveals broad presence of cytoplasmic intron-sequence retaining transcripts in mouse and rat neurons. PLoS One 8:e76194
Bartfai, Tamas; Buckley, Peter T; Eberwine, James (2012) Drug targets: single-cell transcriptomics hastens unbiased discovery. Trends Pharmacol Sci 33:9-16
Buckley, Peter T; Lee, Miler T; Sul, Jai-Yoon et al. (2011) Cytoplasmic intron sequence-retaining transcripts can be dendritically targeted via ID element retrotransposons. Neuron 69:877-84
Kim, Junhyong; Eberwine, James (2010) RNA: state memory and mediator of cellular phenotype. Trends Cell Biol 20:311-8
Bell, Thomas J; Miyashiro, Kevin Y; Sul, Jai-Yoon et al. (2010) Intron retention facilitates splice variant diversity in calcium-activated big potassium channel populations. Proc Natl Acad Sci U S A 107:21152-7