The UBR-1 ubiquitin ligase regulates glutamate metabolism to generate coordinated motor pattern in Caenorhabditis elegans.

UBR1 is an E3 ubiquitin ligase best known for its ability to target protein degradation by the N-end rule. The physiological functions of UBR family proteins, however, remain not fully understood. We found that the functional loss of C. elegans UBR-1 leads to a specific motor deficit: when adult animals generate reversal movements, A-class motor neurons exhibit synchronized activation, preventing body bending. This motor deficit is rescued by removing GOT-1, a transaminase that converts aspartate to glutamate. Both UBR-1 and GOT-1 are expressed and critically required in premotor interneurons of the reversal motor circuit to regulate the motor pattern. ubr-1 and got-1 mutants exhibit elevated and decreased glutamate level, respectively. These results raise an intriguing possibility that UBR proteins regulate glutamate metabolism, which is critical for neuronal development and signaling.

The doublecortin-related gene zyg-8 is a microtubule organizer in Caenorhabditis elegans neurons.

Doublecortin-domain containing (DCDC) genes play key roles in the normal and pathological development of the human brain cortex. The origin of the cellular specialisation and the functional redundancy of these microtubule (MT)-associated proteins (MAPs), especially those of Doublecortin (DCX) and Doublecortin-like kinase (DCLKs) genes, is still unclear. The DCX domain has the ability to control MT architecture and bundling. However, the physiological significance of such properties is not fully understood. To address these issues, we sought post-mitotic roles for zyg-8, the sole representative of the DCX-DCLK subfamily of genes in C. elegans. Previously, zyg-8 has been shown to control anaphase-spindle positioning in one-cell stage embryos, but functions of the gene later in development have not been investigated. Here we show that wild-type zyg-8 is required beyond early embryonic divisions for proper development, spontaneous locomotion and touch sensitivity of adult worms. Consistently, we find zyg-8 expression in the six touch receptor neurons (TRNs), as well as in a subset of other neuronal and non-neuronal cells. In TRNs and motoneurons, zyg-8 controls cell body shape/polarity and process outgrowth and morphology. Ultrastructural analysis of mutant animals reveals that zyg-8 promotes structural integrity, length and number of individual MTs, as well as their bundled organisation in TRNs, with no impact on MT architecture.

Motor neuron synapse and axon defects in a C. elegans alpha-tubulin mutant.

Regulation of microtubule dynamics underlies many fundamental cellular mechanisms including cell division, cell motility, and transport. In neurons, microtubules play key roles in cell migration, axon outgrowth, control of axon and synapse growth, and the regulated transport of vesicles and structural components of synapses. Loss of synapse and axon integrity and disruption of axon transport characterize many neurodegenerative diseases. Recently, mutations that specifically alter the assembly or stability of microtubules have been found to directly cause neurodevelopmental defects or neurodegeneration in vertebrates. We report here the characterization of a missense mutation in the C-terminal domain of C. elegans alpha-tubulin, tba-1(ju89), that disrupts motor neuron synapse and axon development. Mutant ju89 animals exhibit reduction in the number and size of neuromuscular synapses, altered locomotion, and defects in axon extension. Although null mutations of tba-1 show a nearly wild-type pattern, similar axon outgrowth defects were observed in animals lacking the beta-tubulin TBB-2. Genetic analysis reveals that tba-1(ju89) affects synapse development independent of its role in axon outgrowth. tba-1(ju89) is an altered function allele that most likely perturbs interactions between TBA-1 and specific microtubule-associated proteins that control microtubule dynamics and transport of components needed for synapse and axon growth.

SYD-1, a presynaptic protein with PDZ, C2 and rhoGAP-like domains, specifies axon identity in C. elegans.

Axons are defined by the presence of presynaptic specializations at specific locations. We show here that loss-of-function mutations in the C. elegans gene syd-1 cause presynaptic specializations to form in the dendritic processes of GABA-expressing motor neurons during initial differentiation. At a later developmental stage, however, syd-1 is not required for the polarity respecification of a subset of these neurons. The SYD-1 protein contains PDZ, C2 and rho-GTPase activating protein (GAP)-like domains, and is localized to presynaptic terminals in mature neurons. A truncated SYD-1 that lacks the rhoGAP domain interferes with neurite outgrowth and guidance. Our data indicate that syd-1 may be involved in specifying axon identity during initial polarity acquisition.

Getting a GRIP on liprins.

Two papers in this issue of Neuron add a new dimension to our understanding of liprin and LAR RPTP function during synapse formation. present evidence that Dliprin-alpha interacts with Dlar to regulate presynaptic morphogenesis of the Drosophila neuromuscular junction. demonstrate that mammalian liprin-alpha1 forms a complex with the PDZ protein GRIP and LAR in both pre- and postsynaptic compartments of hippocampal neurons and is required for the clustering of the GluR2 glutamate receptor in dendritic spines.