Academic journal article Genetics

PPM-1, a PP2C[alpha]/[Beta] Phosphatase, Regulates Axon Termination and Synapse Formation in Caenorhabditis Elegans

Academic journal article Genetics

PPM-1, a PP2C[alpha]/[Beta] Phosphatase, Regulates Axon Termination and Synapse Formation in Caenorhabditis Elegans

Article excerpt

ABSTRACT The PHR (Pam/Highwire/RPM-1) proteins are evolutionarily conserved ubiquitin ligases that regulate axon guidance and synapse formation in Caenorhabditis elegans, Drosophila, zebrafish, and mice. In C. elegans, RPM-1 (Regulator of Presynaptic Morphology-1) functions in synapse formation, axon guidance, axon termination, and postsynaptic GLR-1 trafficking. Acting as an E3 ubiquitin ligase, RPM-1 negatively regulates a MAP kinase pathway that includes: dlk-1, mkk-4, and the p38 MAPK, pmk-3. Here we provide evidence that ppm-1, a serine/threonine phosphatase homologous to human PP2Ca(PPM1A) and PP2Cb(PPM1B) acts as a second negative regulatory mechanism to control the dlk-1 pathway. We show that ppm-1 functions through its phosphatase activity in a parallel genetic pathway with glo-4 and fsn-1 to regulate both synapse formation in the GABAergic motorneurons and axon termination in the mechanosensory neurons. Our transgenic analysis shows that ppm-1 acts downstream of rpm-1 to negatively regulate the DLK-1 pathway, with PPM-1 most likely acting at the level of pmk-3. Our study provides insight into the negative regulatory mechanisms that control the dlk-1 pathway in neurons and demonstrates a new role for the PP2C/PPM phosphatases as regulators of neuronal development.

THE Pam/Highwire/RPM-1 (PHR) proteins are key regulators of neuronal development that function in synapse formation, axon termination and guidance, axon regeneration, and glutamate receptor trafficking (Schaefer et al. 2000; Wan et al. 2000; Zhen et al. 2000; Burgess et al. 2004; D'Souza et al. 2005; Lewcock et al. 2007; Li et al. 2008; Hammarlund et al. 2009; Park et al. 2009; Po et al. 2010). The PHR protein family includes: human Pam, mouse Phr1, zebrafish esrom/Phr1, Drosophila Highwire and Caenorhabditis elegans Regulator of Presynaptic Morphology (RPM)-1.

PHR proteins function through multiple downstream signaling pathways. In C. elegans, RPM-1 functions as part of an ubiquitin ligase complex that includes the F-box protein, F-box Synaptic Protein (FSN)-1 (Liao et al. 2004). This complex negatively regulates a MAP kinase cascade that includes dual leucine zipper-bearing kinase (dlk-1), map kinase kinase (mkk)-4, p38 map kinase (pmk)-3, map kinase activated protein kinase (mak)-2, and the transcription factor cebp-1 (Nakata et al. 2005; Yan et al. 2009). Drosophila Highwire and mouse Phr1 negatively regulate the ortholog of DLK-1 through a similar mechanism (Collins et al. 2006; Lewcock et al. 2007; Wu et al. 2007; Saiga et al. 2009; Tada et al. 2009). Phr1 also ubiquitinates and negatively regulates the tuberin sclerosis complex (Murthy et al. 2004; D'Souza et al. 2005; Han et al. 2008). RPM-1 positively regulates signaling through a Rab GTPase pathway by binding to Gut Granule Loss (GLO)-4 (Grill et al. 2007).

While RPM-1 negatively regulates the DLK-1 pathway, there are a number of reasons to suspect that the DLK-1 pathway may also be controlled by other negative regulatory mechanisms. First, overexpression of dlk-1 causes more dramatic phenotypes than rpm-1 loss of function (lf), including uncoordinated movement and small body size (Nakata et al. 2005; Abrams et al. 2008). Second, the dlk-1 pathway consists of five signaling molecules providing numerous points where regulation might occur. Third, ubiquitination is a relatively slow-acting mechanism to restrict DLK-1 signaling. The observation that UEV-3 is a possible positive regulator of PMK-3 (Trujillo et al. 2010) further supports the idea that multiple mechanisms may control the DLK-1 pathway.

There is a large body of evidence that MAP kinases are negatively regulated by phosphatases including MAP kinasespecific phosphatases, and broad-acting PP2C/PPM family phosphatases (Lu and Wang 2008; Shi 2009; Bermudez et al. 2010). While MAP kinases are known to function in neurons (Ji et al. 2009; Samuels et al. 2009), the negative regulatory phosphatases that control MAP kinase signaling in neurons remain relatively poorly understood. …

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