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Review
. 2014 Jun;52(6):544-54.
doi: 10.1002/dvg.22744. Epub 2014 Feb 7.

Asymmetric neural development in the Caenorhabditis elegans olfactory system

Yi-Wen Hsieh  1 , Amel Alqadah, Chiou-Fen Chuang
Affiliations
Review

Asymmetric neural development in the Caenorhabditis elegans olfactory system

Yi-Wen Hsieh et al. Genesis. 2014 Jun.

Abstract

Asymmetries in the nervous system have been observed throughout the animal kingdom. Deviations of brain asymmetries are associated with a variety of neurodevelopmental disorders; however, there has been limited progress in determining how normal asymmetry is established in vertebrates. In the Caenorhabditis elegans chemosensory system, two pairs of morphologically symmetrical neurons exhibit molecular and functional asymmetries. This review focuses on the development of antisymmetry of the pair of amphid wing "C" (AWC) olfactory neurons, from transcriptional regulation of general cell identity, establishment of asymmetry through neural network formation and calcium signaling, to the maintenance of asymmetry throughout the life of the animal. Many of the factors that are involved in AWC development have homologs in vertebrates, which may potentially function in the development of vertebrate brain asymmetry.

Keywords: AWC neurons; antisymmetry; calcium signaling; gap junctions; lateral inhibition; left-right neuronal asymmetry; nematode; stochastic cell fate.

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Figures

FIG. 1
FIG. 1. The C. elegans left and right AWC olfactory neurons differentiate asymmetrically at molecular and functional levels
(a) Top panel: DIC image of an adult C. elegans with anterior to the left and dorsal to the top. Scale bar, 50 μm. Bottom panel: Fluorescent micrograph image of the AWCON neuron expressing str-2p::TagRFP and the AWCOFF neuron expressing srsx-3p::GFP, taken from the head region outlined in the top panel. Arrows indicate the cell body of AWC neurons. Asterisks indicate AWB neurons. Scale bar, 10 μm. (b) Developmental timeline of AWC asymmetry.
FIG. 2
FIG. 2. A transient embryonic gap junction neural network coordinates stochastic AWC asymmetry
(a) Prior to cell-cell communication, both AWC neurons have high intracellular calcium levels and symmetrically exist in the default AWCOFF state. (b) AWC, ASH, AFD, and AWB sensory neurons are part of a transient embryonic neural network connected by NSY-5 gap junctions and contribute to the decision making of stochastic AWC asymmetry. Differences in calcium levels between left and right sides of neuronal pairs promote the AWCON or AWCOFF subtype, depending on the cellular context. AWC asymmetry is stochastic, and this figure illustrates the case when AWCON is on the left and AWCOFF is on the right.
FIG. 3
FIG. 3. Establishment of AWC asymmetry
(a–c) AWC asymmetry is stochastic, and this figure illustrates the case when AWCON is on the left and AWCOFF is on the right. Molecules in red represent AWCOFF promoting, those in green represent AWCON promoting, and those in white indicate inactive or less active molecules. Question marks represent steps in which the molecular mechanism is unknown. Steps in the AWCOFF neuron are proposed to take place sequentially, however the steps in AWCON may not occur in the sequence proposed in the illustration, as the sequence of events has not yet been determined. Default AWCOFF (right): (a) 1. Calcium enters the cell through voltage-gated calcium channels. 2. Calcium influx stimulates UNC-43 (CaMKII), allowing the assembly of a calcium-signaling complex consisting of UNC-43 (CaMKII), the TIR-1 (Sarm1) adaptor protein, and NSY-1 (MAPKKK). The assembly of the calcium-signaling complex brings these molecules in close proximity of each other, so that UNC-43 (CaMKII) phosphorylates NSY-1 (MAPKKK) and then NSY-1 (MAPKKK) phosphorylates SEK-1 (MAPKK). (b) 3. Microtubules transport the UNC-43 (CaMKII)/TIR-1 (Sarm1)/NSY-1 (MAPKKK) calcium-signaling complex to synapses in AWC axons via an unidentified “X” motor protein. The UNC-104 kinesin motor protein in the contralateral AWC transports an unknown molecule, which is required for the transport of the TIR-1 signaling complex in the AWCOFF cell to specify the AWCOFF subtype. (c) 4. Proposed retrograde signaling, mediated by an unidentified “Y” motor protein, may convey the lateral signaling between the two AWC cells from the synapses to regulate gene expression in the cell body. 5. The AWCOFF marker srsx-3 is transcribed, and the expression of the AWCON marker str-2 is suppressed. Induced AWCON (left): (a) 1. Axon guidance molecules contribute to AWC axon outgrowth, allowing chemical synapse formation and communication between the two cells. 2. NSY-5 gap junctions and NSY-4 claudin-like adhesions act in parallel to inhibit voltage-gated calcium channels, resulting in a low level of intracellular calcium. (b) 3. NSY-5 and NSY-4 stabilize mature mir-71 miRNA, which inhibits calcium signaling through targeting the 3′ TUR of tir-1/Sarm1. (c) 4. OLRN-1 Raw repeat protein inhibits UNC-43 (CaMKII). 5. The AWCON marker str-2 is expressed, and the AWCOFF marker srsx-3 is inhibited.
FIG. 4
FIG. 4. Maintenance of AWC asymmetry
AWC asymmetry is stochastic, and this figure illustrates the case when AWCON is on the left and AWCOFF is on the right. Molecules in red represent AWCOFF promoting, those in green represent AWCON promoting, and those in white indicate inactive or less active molecules. Molecules in orange, yellow, and blue represent the three distinct mechanisms used for the maintenance of AWC asymmetry. GC, guanylyl cyclase. Left: The AWCON subtype is maintained using two mechanisms: olfactory transduction (ODR-1 and ODR-3 represented in orange maintain str-2 expression), and transcriptional regulation (HMBX-1 and NSY-7 represented in yellow repress srsx-3 expression). Right: The AWCOFF subtype (srsx-3 expression) is maintained using olfactory transduction molecules (TAX-4, ODR-1, and ODR-3 represented in orange) and TGF-β signaling (DAF-7 and DAF-1 represented in blue).
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