Neuronal Development in <i>Caenorhabditis elegans</i> Is Regulated by Inhibition of an MLK MAP Kinase Pathway

Baker, Scott T.; Turgeon, Shane M.; Tulgren, Erik D.; Wigant, Jeanne; Rahimi, Omeed; Opperman, Karla J.; Grill, Brock

doi:10.1534/genetics.114.170589

Cited by 11 publications

(18 citation statements)

References 15 publications

(43 reference statements)

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“…Several downstream proteins that mediate the function of RPM-1 in neuronal development have been identified ( Baker et al 2014 , 2015 ; Grill et al 2007 , 2012 ; Liao et al 2004 ; Nakata et al 2005 ; Tulgren et al 2014 ; Yan et al 2009 ). For example, RPM-1 positively activates GLO-4 to regulate the GLO-1 Rab GTPase ( Figure 6A ) ( Grill et al 2007 ).…”

Section: Resultsmentioning

confidence: 99%

“…After more than a decade of research, the PHR proteins have emerged as key, conserved regulators of neuronal development and axon degeneration ( Conforti et al 2014 ; Po et al 2010 ). Numerous downstream effector proteins and pathways that mediate PHR protein function have also been discovered ( Baker et al 2014 , 2015 ; Collins et al 2006 ; Grill et al 2007 , 2012 ; Liao et al 2004 ; Murthy et al 2004 ; Nakata et al 2005 ; Tian et al 2011 ; Tulgren et al 2014 ; Xiong et al 2012 ; Yan et al 2009 ). Despite this important progress, a lingering question has remained: how does the function of PHR proteins during development impact behavior?…”

Section: Discussionmentioning

confidence: 99%

“…The PHR proteins, named for the orthologs PAM (MYCBP2) in Homo sapiens , Highwire in Drosophila melanogaster , and RPM-1 in Caenorhabditis elegans , are important regulators of neuronal development (reviewed in Po et al 2010 ). PHR proteins function as intracellular signaling hubs that regulate the activity of multiple downstream signaling pathways that include: MAP kinases ( Baker et al 2015 ; Collins et al 2006 ; Lewcock et al 2007 ; Nakata et al 2005 ; Nix et al 2011 ; Yan et al 2009 ), the PP2C phosphatase PPM-2 that inhibits the DLK-1 MAP3K in C. elegans ( Baker et al 2014 ), the tuberous sclerosis complex ( Han et al 2012 ; Murthy et al 2004 ), the microtubule binding protein RAE-1 ( Grill et al 2012 ; Tian et al 2011 ), Rab signaling ( Grill et al 2007 ), and beta-catenin signaling ( Tulgren et al 2014 ). In C. elegans , rpm-1 loss-of-function (lf) mutants have strong defects in neuronal development.…”

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confidence: 99%

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Developmental Function of the PHR Protein RPM-1 Is Required for Learning inCaenorhabditis elegans

Giles

Opperman

Rankin

et al. 2015

G3 Genes|Genomes|Genetics

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The PAM/Highwire/RPM-1 (PHR) proteins are signaling hubs that function as important regulators of neural development. Loss of function in Caenorhabditis elegans rpm-1 and Drosophila Highwire results in failed axon termination, inappropriate axon targeting, and abnormal synapse formation. Despite broad expression in the nervous system and relatively dramatic defects in synapse formation and axon development, very mild abnormalities in behavior have been found in animals lacking PHR protein function. Therefore, we hypothesized that large defects in behavior might only be detected in scenarios in which evoked, prolonged circuit function is required, or in which behavioral plasticity occurs. Using quantitative approaches in C. elegans, we found that rpm-1 loss-of-function mutants have relatively mild abnormalities in exploratory locomotion, but have large defects in evoked responses to harsh touch and learning associated with tap habituation. We explored the nature of the severe habituation defects in rpm-1 mutants further. To address what part of the habituation circuit was impaired in rpm-1 mutants, we performed rescue analysis with promoters for different neurons. Our findings indicate that RPM-1 function in the mechanosensory neurons affects habituation. Transgenic expression of RPM-1 in adult animals failed to rescue habituation defects, consistent with developmental defects in rpm-1 mutants resulting in impaired habituation. Genetic analysis showed that other regulators of neuronal development that function in the rpm-1 pathway (including glo-4, fsn-1, and dlk-1) also affected habituation. Overall, our findings suggest that developmental defects in rpm-1 mutants manifest most prominently in behaviors that require protracted or plastic circuit function, such as learning.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Developmental Function of the PHR Protein RPM-1 Is Required for Learning inCaenorhabditis elegans

Giles

Opperman

Rankin

et al. 2015

G3 Genes|Genomes|Genetics

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“…elegans regulator of presynaptic morphology 1 (RPM-1) is an intracellular signaling hub that regulates axon termination, and is orthologous to Drosophila Highwire, mouse Phr1 and human Pam/ MYCBP2 (Borgen et al, 2017;Feoktistov and Herman, 2016;Grill et al, 2016;Opperman and Grill, 2014;Schaefer et al, 2000). RPM-1 acts as a ubiquitin ligase to inhibit MAP3K proteins, such as DLK-1 and MLK-1 (Baker et al, 2015;Collins et al, 2006;Nakata et al, 2005). Notably, RPM-1 also uses signaling mechanisms that are independent of its ubiquitin ligase activity (Baker et al, 2014;Grill et al, 2007;Grill et al, 2012;Tulgren et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

RPM-1 regulates axon termination by affecting growth cone collapse and microtubule stability

2017

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Axon termination is essential for efficient and accurate nervous system construction. At present, relatively little is known about how growth cone collapse occurs prior to axon termination Using the mechanosensory neurons of, we found collapse prior to axon termination is protracted, with the growth cone transitioning from a dynamic to a static state. Growth cone collapse prior to termination is facilitated by the signaling hub RPM-1. Given the prominence of the cytoskeleton in growth cone collapse, we assessed the relationship between RPM-1 and regulators of actin dynamics and microtubule stability. Our results reveal several important findings about how axon termination is orchestrated: (1) RPM-1 functions in parallel to RHO-1 and CRMP/UNC-33, but is suppressed by the Rac isoform MIG-2; (2) RPM-1 opposes the function of microtubule stabilizers, including tubulin acetyltransferases; and (3) genetic epistasis suggests the microtubule-stabilizing protein Tau/PTL-1 potentially inhibits RPM-1. These findings provide insight into how growth cone collapse is regulated during axon termination , and suggest that RPM-1 signaling destabilizes microtubules to facilitate growth cone collapse and axon termination.

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“…Initial studies in Drosophila showed that Highwire inhibition of Wallenda/Dlk impacted the JNK ortholog, Basket, and the transcription factor c-Fos [ 48 ]. While these initial studies suggested that different MAP kinase pathways might be regulated by RPM-1 and Highwire, this was not the case as subsequent genetic analysis indicated that RPM-1 regulates a second MAPK pathway composed of the MAP3K MLK-1, the MAP2K MEK-1 (MKK7 ortholog) and the JNK isoform KGB-1 [ 46 , 55 , 56 ] (Fig. 1a ).…”

Section: Introductionmentioning

confidence: 99%

The PHR proteins: intracellular signaling hubs in neuronal development and axon degeneration

2016

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During development, a coordinated and integrated series of events must be accomplished in order to generate functional neural circuits. Axons must navigate toward target cells, build synaptic connections, and terminate outgrowth. The PHR proteins (consisting of mammalian Phr1/MYCBP2, Drosophila Highwire and C. elegans RPM-1) function in each of these events in development. Here, we review PHR function across species, as well as the myriad of signaling pathways PHR proteins regulate. These findings collectively suggest that the PHR proteins are intracellular signaling hubs, a concept we explore in depth. Consistent with prominent developmental functions, genetic links have begun to emerge between PHR signaling networks and neurodevelopmental disorders, such as autism, schizophrenia and intellectual disability. Finally, we discuss the recent and important finding that PHR proteins regulate axon degeneration, which has further heightened interest in this fascinating group of molecules.

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Neuronal Development in Caenorhabditis elegans Is Regulated by Inhibition of an MLK MAP Kinase Pathway

Cited by 11 publications

References 15 publications

Developmental Function of the PHR Protein RPM-1 Is Required for Learning inCaenorhabditis elegans

Developmental Function of the PHR Protein RPM-1 Is Required for Learning inCaenorhabditis elegans

RPM-1 regulates axon termination by affecting growth cone collapse and microtubule stability

The PHR proteins: intracellular signaling hubs in neuronal development and axon degeneration

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