Research Overview: Left-right asymmetry in brain development
Clinical implications of human brain asymmetry
Left-right differences in anatomical structures and functions of the central nervous system are present throughout the animal kingdom. Left-right asymmetry has been implicated as an important aspect of normal brain development and function in humans, as reduction or reversal of brain asymmetry has been linked to neurological disorders including developmental dyslexia, schizophrenia, depression and autism. However, the molecular mechanisms that underlie the brain asymmetry are unclear. We study the simple nervous system in the small roundworm Caenorhabditis elegans, composed of just 302 neurons, to uncover fundamental mechanisms that are likely to be used in our own brain.
Left-right asymmetry in the C. elegans sensory system
C. elegans can sense hundreds of different odors, discriminate between them, and generate different behaviors in response to different odors. The left and right Amphid Wing ‘C’ (AWC) neurons of the C. elegans olfactory system are bilaterally symmetric with regard to their morphological and anatomical features, develop asymmetry at the molecular and functional level. The candidate odorant receptor gene str-2 is randomly expressed in only one of the two AWC neurons. The AWC neurons are distinguished by whether or not they express the candidate odorant receptor gene str-2::GFP as AWCON and AWCOFF (Figure 1). Our research has been focusing on signaling pathways that create AWC neuronal asymmetry, which revealed an important role of a transient, embryonic gap junction neural network and synaptic signaling molecules in neuronal maturation. AWC neuronal asymmetry is determined in a stochastic manner through the modulation of calcium signaling by NSY-5 gap junctions and synapse-mediated cell-cell communication across the midline (Figure 2). AWC asymmetry seems to be evolutionarily advantageous since it allows the worm to sense multiple odors using a limited number of olfactory sensory neurons.
We are extending these discoveries in several directions to further define the logic of cell-cell communication and signaling events that specify left-right neuronal asymmetry. Our current research is focused on the following questions:
- What transient signal mediates cell-cell communication across the NSY-5 gap junction network to specify left-right neuronal asymmetry?
- How is brief embryonic communication through gap junctions translated into a permanent change in neuronal function?
- How is a signaling complex localized at chemical synapses, where cell-cell communication occurs, and retrogradely transported to the cell body, where asymmetric gene expression is regulated?
- Does the NSY-5 gap junction network have a broad impact on other neuron pairs in setting up their left-right asymmetries?
Significance of our research
The establishment of C. elegans left-right AWC neuronal asymmetry by transient NSY-5 gap junctions and the genetically downstream calcium-regulated signaling pathway provides an attractive system to elucidate the molecular mechanisms of cell-cell communication in brain asymmetry. Studies in C. elegans have led to the discovery of many important biological processes that are conserved from worms to humans including axon guidance, programmed cell death, RNA interference, and miRNA-guided posttranscriptional gene regulation. Our study of left-right asymmetric neuronal specification in C. elegans will shed light on the mechanisms of human brain asymmetry and could lead to the development of therapeutic strategies for treating laterality-based neurological disorders.
Publications
Taylor R*, Hsieh Y-W*, Gamse J, Chuang C-F. Making a difference together: reciprocal interactions in C.elegans and zebrafish asymmetric neural development. Development 2010;137:681-91. *These two authors contributed equally to this work.
Gabel CV, Antonie F, Chuang C-F, Samuel AD, Chang C. Distinct cellular and molecular mechanisms mediate initial axon development and adult-stage axon regeneration in C. elegans. Development 2008;135:1129-36.
Chuang C-F, VanHoven MK, Fetter RD, Verselis VK, Bargmann CI. An innexin-dependent cell network establishes left-right neuronal asymmetry in C. elegans. Cell 2007;129:787-99. (Preview: Gap Junctions Provide New Links in Left-Right Patterning. Cell 2007;129:645-47.)
Chuang C-F, Bargmann CI. A Toll-interleukin 1 repeat protein at the synapse specifies asymmetric odorant receptor expression via ASK1 MAPKKK signaling. Genes & Dev 2005;19:270-81.
Chuang C-F, Meyerowitz EM. Specific and heritable genetic interference by double-stranded RNA in Arabidopsis thaliana. Proc. Natl. Acad. Sci. 2000;97:4985-90.
Chuang C-F, Running MP, Williams RW, Meyerowitz EM. The PERIANTHIA gene encodes a bZIP protein involved in the determination of floral organ number in Arabidopsis thaliana. Genes & Dev. 1999;13:334-44.
Work in the Lab
View details about our available positions:
- Postdoctoral Position
- Laboratory Aide
- Graduate Students
Contact Us
The Chuang Laboratory is part of the Division of Developmental Biology at Cincinnati Children's Hospital Research Foundation. The lab is located in Location S, Room S3.532/S3.533. Dr. Chuang's office is located in S3.405.
Division of Developmental Biology
Children's Hospital Research Foundation
3333 Burnet Avenue, MLC 7007
Cincinnati, OH 45229
Email: Chiou-Fen.Chuang@cchmc.org
Tel: 513-803-0046 (Chuang office)
513-803-0760 (lab office)
513-636-8117 (lab)
Fax: 513-636-4317
