UNC-55, an Orphan Nuclear Hormone Receptor, Orchestrates Synaptic Specificity among Two Classes of Motor Neurons inCaenorhabditis elegans

Abstract

Loss of UNC-55 function in the nematode Caenorhabditis elegans causes one motor neuron class, the ventral D (VD) motor neurons, to adopt the synaptic pattern of another motor neuron class, the dorsal D (DD) motor neurons. Here we show that unc-55 encodes a member of the nuclear hormone receptor gene family that is similar to the vertebrate chicken ovalbumin upstream promoter transcription factors. Although the VD and DD motor neuron classes arise from different lineages at different developmental stages, they share a number of structural and functional features that appear to be the product of identical genetic programs. UNC-55 is expressed in the VD but not the DD motor neurons to modify this genetic program and to create the synaptic pattern that distinguishes the two motor neuron classes from one another.Key words: synaptic specificity; C. elegans; motor neurons; nuclear hormone receptor; neuromuscular junction; unc-55The complexity of synaptic patterns present in mature nervous systems raises a f undamental question: how does a finite amount of genetic material create the synaptic diversity present in even the simplest nervous systems? Several lines of evidence suggest that the genetic programs are less diverse than would be predicted by the multitude of synaptic patterns. For example, in the development of layer 5 neurons in the mammalian cortex, visual and motor cortical neurons initially extend projections to the same subcortical regions, including the spinal cord. Subsequently, the structural and f unctional differences that distinguish these neurons emerge because of differential pruning of collateral branches (O'Leary and Terashima, 1988). A conceptually similar example has been reported in the nematode Caenorhabditis elegans: two sets of mechanosensory neurons initiate either forward or backward locomotion by activating different neural circuits based on whether the animal is touched on the anterior or posterior part of the body (Chalfie and Au, 1989). However, the same genetic program regulates the differentiation and f unction of the two circuits (Way and Chalfie, 1988;Xue et al., 1993). In both examples a common genetic program plus features associated with the relative positions of the neurons cause them to form distinctive synaptic patterns (Chalfie et al., 1983;Walthall and Chalfie, 1988). Our goal is to investigate the mechanisms responsible for modifying the common genetic programs of neurons to create different synaptic specificities.The precisely defined sets of nerve and muscle cells responsible for locomotion in C. elegans allow genetic and cellular manipulations that provide a unique opportunity for investigating the generation of specific synaptic patterns. The sinuous forward and backward locomotion exhibited by C. elegans is produced by two neural circuits; one dedicated to forward movement and the other dedicated to backward movement (Chalfie et al., 1985). These two circuits converge on the dorsal and ventral body wall muscles and two classes of inhibitory motor neurons: 6 dorsal D (...

Regulation of chemosensory and GABAergic motor neuron development by theC. elegans Aristaless/Arxhomologalr-1

“…In unc-55 mutants, the VDs adopt a DD wiring pattern, and this change in innervation pattern is believed to underlie the locomotion defects of unc-55 mutants (Walthall and Plunkett, 1995;Zhou and Walthall, 1998). In agreement with a VD-to-DD fate transformation in unc-55 mutants, we observed ectopic flp-13::gfp expression in unc-55(e402) mutant adults but not in L1 larvae (Fig.…”

“…The COUP transcription factor UNC-55 has been previously shown to prevent the expression of the DD synaptic pattern in the VD MNs (Walthall and Plunkett, 1995;Zhou and Walthall, 1998). We have shown that similar to ALR-1, UNC-55 also represses expression of flp-13::gfp in the VD MNs, although, unlike UNC-55, ALR-1 does not affect the synaptic pattern of VD motoneurons.…”

“…The UNC-55 COUP-TF-like nuclear hormone receptor has been shown to be expressed in the VD MNs, where it acts to repress DD MN identity (Walthall and Plunkett, 1995;Zhou and Walthall, 1998). In unc-55 mutants, the VDs adopt a DD wiring pattern, and this change in innervation pattern is believed to underlie the locomotion defects of unc-55 mutants (Walthall and Plunkett, 1995;Zhou and Walthall, 1998).…”

Neural circuit rewiring: insights from DD synapse remodeling

“…2 The COUP-TF nuclear hormone receptor UNC-55 is expressed in the VD neurons and restricts them from remodeling their synapses. 6,7 Ectopic expression of UNC-55 in L1 DD neurons can prevent their remodeling, consistent with a model that lack of UNC-55 in DD neurons enables their ability to remodel. 8 Transcriptional targets of UNC-55 include the Iroquois-like homeodomain protein IRX-1 and the Hunchback-like transcription factor HBL-1, both of which are normally expressed in the DD neurons and promote remodeling.…”

“…Indeed, an example of synapse refinement in the absence of axon growth was described in the mammalian central nervous system, where imaging of individual axonal arbors of retinal ganglion cells showed that retinogeniculate synapse remodeling can occur without axon retraction. 33 Four decades after John White's seminal work, we have learned a great deal about DD remodeling, which has provided a rich platform to study the temporal cues 4,6,7,9,10,14,17 as well as the cellular mechanisms that underlie this complete inversion of synaptic connectivity. [22][23][24] Our findings have also revealed a novel role of dynamic MTs in regulating synaptic vesicle transport in the absence of neurite growth or pruning.…”