The scientific approach to the human brain has always been limited by the sheer number of neurons: estimated at 10 billion to 1 trillion neurons (Williams and Herrup 1998). Cross sections through a human brain reveal carefully segregated centers that can regulate precise bodily functions or complex emotions. A comparison between the hemispheres uncovers many L/R differences. For example, Broca?s area, an area which codes for language, is larger on the left side of most right-handed, normally developed individuals (Foss? et al 2004). Asymmetry is not unique to the human brain: lateralized differences in brain architecture, gene expression, and function can be witnessed across the vertebrate clade (Concha and Wilson 2001). We have implicated a secretory pathway gene as a contributing factor to developing asymmetry in the zebrafish. This gene, sec61alpha1, is the major subunit of the vertebrate translocon, a pore on the endoplasmic reticulum which accepts newly translated peptides into the secretory pathway (Rapoport 2007). We doubt that the pore itself has neurogenic capacity;it likely regulates early components of the asymmetry pathway. Developmental genetics represents one reductionist discipline with potential to help decode the mysteries of the vertebrate nervous system. Utilizing a model organism such as the zebrafish, we can monitor asymmetric brain development in a less intricate environment, yet retain high conservation of gene identity to human homologs. The zebrafish is amenable to both gain and loss of function techniques, and has powerful transgenic monitoring capacity. This allows us to visualize early cell behaviors, connections, and movements that contribute to early brain development, with careful reference to the contributions of individual genes. In my research, I plan to examine several possible mechanisms by which the sec61alpha1 gene impacts habenular neurogenesis in the zebrafish. I will first examine the effects of the translocon on habenular subnuclear neurogenesis, which can be distinguished through in situ hybridization for specific marker genes, birth-date analysis through BrdU incorporation, and time-lapse microscopy of progenitor cell migration from the ventral epithalamus. Next, I will focus on the epithalamic roof plate, a crucial signaling center in the developing nervous system. We believe the roof plate influences habenular progenitor migration, and that the Notch signaling family may regulate roof plate formation. in situ hybridization for roof plate markers and laser ablation of the roof plate with illuminate the impact of this dorsal structure in both sec61alpha1 and Notch pathway mutants, as compared to wild type. Finally, we will investigate whether sec61alpha1 acts in the habenular progenitors or in the roof plate, through genetic mosaic analysis, RNA rescue, and habenular-specific expression of the gene.

Public Health Relevance

The left and right hemispheres of the human brain are not created equal: some regions of the brain control behaviors unilaterally. These L/R differences include specialized functions, such as the left hemisphere-specific coding of language (De Foss? et al 2004), and it has been suggested that asymmetry is disrupted in schizophrenia (Mitchell and Crow 2005), autism (De Foss? et al 2004), and dyslexia (Leonard and Eckert 2008). By characterizing the highly conserved genes that contribute to the development of asymmetry in zebrafish, we can extrapolate to their human counterparts for a better understanding of how and why asymmetry is generated in the brain.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-F03A-F (20))
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Riddle, Robert D
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Vanderbilt University Medical Center
Schools of Arts and Sciences
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Doll, Caleb A; Burkart, Jarred T; Hope, Kyle D et al. (2011) Subnuclear development of the zebrafish habenular nuclei requires ER translocon function. Dev Biol 360:44-57