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 olfactory 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 asymmetrically at the molecular and functional level. The two AWC cells express different odorant receptors and sense different odors (Figures 1, 2). The AWC neurons are distinguished by whether or not they express the candidate odorant receptor gene str-2::GFP as AWCON and AWCOFF (Figures 1, 2). Genetic studies indicate that AWCOFF and AWCON are specified through a calcium-regulated MAPK signaling pathway (Figure 2) in a stochastic manner. Differential calcium levels between the two AWC cells determine their cell fates. The AWC with a higher calcium level remains as the default AWCOFF, while the AWC with the lower calcium level becomes the induced AWCON. AWC asymmetry seems to be evolutionarily advantageous since it allows the worm to sense multiple odors using a limited number of olfactory sensory neurons.
Cell-cell communication through a transient gap junction-coupled cell network establishes long-lasting left-right neuronal asymmetry
Our research has been focusing on signaling pathways that create AWC neuronal asymmetry. Our study revealed an important role of a transient, embryonic NSY-5 gap junction neural network and synaptic signaling molecules in neuronal maturation. The NSY-5 network is defined by the 18 pairs of nsy-5-expressing neurons, including AWCs, that are likely to be linked by gap junctions. We found that intercellular calcium signaling between AWCs and non-AWCs in the NSY-5 network helps AWC neurons fine-tune the signaling for the establishment of precise asymmetry (Chuang et. al., Cell 2007; Schumacher et al., Development 2012). We also found that the conserved TIR-1/Sarm1 adaptor protein assembles a Ca2+-signaling complex at axonal synapses to specify AWC asymmetry in a manner dependent on microtubules and motor proteins (Chuang and Bargmann Genes & Development 2005; Chang et al., Development 2010).
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:
1. How is brief embryonic communication through gap junctions translated into a permanent change in neuronal function?
2. How is calcium signaling inhibited in the induced AWCON cell by NSY-5?
3. 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?
4. Do other neurons in the NSY-5 network also display asymmetric differentiation? 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.
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 olfactory 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 asymmetrically at the molecular and functional level. The two AWC cells express different odorant receptors and sense different odors (Figures 1, 2). The AWC neurons are distinguished by whether or not they express the candidate odorant receptor gene str-2::GFP as AWCON and AWCOFF (Figures 1, 2). Genetic studies indicate that AWCOFF and AWCON are specified through a calcium-regulated MAPK signaling pathway (Figure 2) in a stochastic manner. Differential calcium levels between the two AWC cells determine their cell fates. The AWC with a higher calcium level remains as the default AWCOFF, while the AWC with the lower calcium level becomes the induced AWCON. AWC asymmetry seems to be evolutionarily advantageous since it allows the worm to sense multiple odors using a limited number of olfactory sensory neurons.
Cell-cell communication through a transient gap junction-coupled cell network establishes long-lasting left-right neuronal asymmetry
Our research has been focusing on signaling pathways that create AWC neuronal asymmetry. Our study revealed an important role of a transient, embryonic NSY-5 gap junction neural network and synaptic signaling molecules in neuronal maturation. The NSY-5 network is defined by the 18 pairs of nsy-5-expressing neurons, including AWCs, that are likely to be linked by gap junctions. We found that intercellular calcium signaling between AWCs and non-AWCs in the NSY-5 network helps AWC neurons fine-tune the signaling for the establishment of precise asymmetry (Chuang et. al., Cell 2007; Schumacher et al., Development 2012). We also found that the conserved TIR-1/Sarm1 adaptor protein assembles a Ca2+-signaling complex at axonal synapses to specify AWC asymmetry in a manner dependent on microtubules and motor proteins (Chuang and Bargmann Genes & Development 2005; Chang et al., Development 2010).
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:
1. How is brief embryonic communication through gap junctions translated into a permanent change in neuronal function?
2. How is calcium signaling inhibited in the induced AWCON cell by NSY-5?
3. 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?
4. Do other neurons in the NSY-5 network also display asymmetric differentiation? 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.