PHRs: bridging axon guidance, outgrowth and synapse development

Current Opinion in Neurobiology

Volumn 20, Issue 1, 2010, Pages 100-107

  Po, Michelle D ^a,c   Hwang, Christine ^b,c   Zhen, Mei ^a,b,c  

^a UNIVERSITY OF TORONTO   (Canada)

^b UNIVERSITY OF TORONTO   (Canada)

^c MOUNT SINAI HOSPITAL   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

BASIC LEUCINE ZIPPER TRANSCRIPTION FACTOR; BONE MORPHOGENETIC PROTEIN; CAENORHABDITIS ELEGANS PROTEIN; CULLIN; DROSOPHILA PROTEIN; ESROM; F BOX PROTEIN; MITOGEN ACTIVATED PROTEIN KINASE; MITOGEN ACTIVATED PROTEIN KINASE KINASE; MITOGEN ACTIVATED PROTEIN KINASE P38; MYC PROTEIN; NETRIN; PROTEIN FSN 1; PROTEIN HIGHWIRE; PROTEIN RPM 1; ROUNDABOUT RECEPTOR; S PHASE KINASE ASSOCIATED PROTEIN; TUBERIN; UBIQUITIN PROTEIN LIGASE E3; UNCLASSIFIED DRUG; WALLENDA; ZEBRAFISH PROTEIN;

CELL MIGRATION; DOWN REGULATION; ENDOSOME; HUMAN; NERVE FIBER; NERVE FIBER GROWTH; NERVE FIBER REGENERATION; NEUROMUSCULAR SYNAPSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN MOTIF; PROTEIN PROCESSING; PROTEIN PROTEIN INTERACTION; REVIEW; RNA INTERFERENCE; SYNAPSE; SYNAPTOGENESIS;

ADAPTOR PROTEINS, SIGNAL TRANSDUCING; ANIMALS; AXONS; CARRIER PROTEINS; CELL MOVEMENT; DENDRITES; HUMANS; NEURONS; PSEUDOPODIA; SYNAPSES; UBIQUITIN-PROTEIN LIGASES;

EID: 76749119511     PISSN: 09594388     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.conb.2009.12.007     Document Type: Review

References (41)

1. Guo Q., Xie J., Dang C.V., Liu E.T., and Bishop J.M. Identification of a large Myc-binding protein that contains RCC1-like repeats. Proc Natl Acad Sci USA 95 (1998) 9172-9177
2. ••], this study first described the physiological roles of PHR proteins. This study identified synaptic defects, with both overdifferentiation and underdifferentiated GABAergic synapses, in rpm-1 mutants.
3. ••], this study first described the physiological roles of PHR proteins. In rpm-1 mutants, mechanosensory axons overshoot their targets and fail to accumulate vesicles at synapses.
4. ••], this study first described the physiological roles of PHR proteins. Drosophila highwire mutants show excessive branching and sprouting at glutamatergic NMJs. These mutant NMJs have functional defects, with decreased quantal size and decreased evoked response.
5. D'Souza J., Hendricks M., Le Guyader S., Subburaju S., Grunewald B., Scholich K., and Jesuthasan S. Formation of the retinotectal projection requires Esrom, an ortholog of PAM (protein associated with Myc). Development 132 (2005) 247-256. The authors show that mutations in zebrafish Esrom affect the targeting of retinal axons. This study reveals the prominent role of the vertebrate PHR in axon navigation. esrom defects associate with an elevated amount of phosphorylated TSC2/Tuberin.
6. Karlstrom R.O., Trowe T., Klostermann S., Baier H., Brand M., Crawford A.D., Grunewald B., Haffter P., Hoffmann H., Meyer S.U., et al. Zebrafish mutations affecting retinotectal axon pathfinding. Development 123 (1996) 427-438
7. Burgess R.W., Peterson K.A., Johnson M.J., Roix J.J., Welsh I.C., and O'Brien T.P. Evidence for a conserved function in synapse formation reveals Phr1 as a candidate gene for respiratory failure in newborn mice. Mol Cell Biol 24 (2004) 1096-1105
8. Li H., Kulkarni G., and Wadsworth W.G. RPM-1, a Caenorhabditis elegans protein that functions in presynaptic differentiation, negatively regulates axon outgrowth by controlling SAX-3/robo and UNC-5/UNC5 activity. J Neurosci 28 (2008) 3595-3603. This study reveals complex genetic interactions between rpm-1 and axon guidance mutants. The localization and expression of specific receptors for axon guidance are affected in rpm-1 mutants, suggesting that RPM-1 affects axon outgrowth partially through the regulation of guidance receptors.
9. Hammarlund M., Nix P., Hauth L., Jorgensen E.M., and Bastiani M. Axon regeneration requires a conserved MAP kinase pathway. Science 323 (2009) 802-806. The DLK MAPK pathway is essential for motor axon regeneration after injury. Mutations in fsn-1 or rpm-1 enhance axon regeneration and an overexpression of RPM-1 inhibits regeneration.
10. Abrams B., Grill B., Huang X., and Jin Y. Cellular and molecular determinants targeting the Caenorhabditis elegans PHR protein RPM-1 to perisynaptic regions. Dev Dyn 237 (2008) 630-639
11. Wu C., Wairkar Y.P., Collins C.A., and DiAntonio A. Highwire function at the Drosophila neuromuscular junction: spatial, structural, and temporal requirements. J Neurosci 25 (2005) 9557-9566
12. Ehnert C., Tegeder I., Pierre S., Birod K., Nguyen H.V., Schmidtko A., Geisslinger G., and Scholich K. Protein associated with Myc (PAM) is involved in spinal nociceptive processing. J Neurochem 88 (2004) 948-957
13. Lewcock J.W., Genoud N., Lettieri K., and Pfaff S.L. The ubiquitin ligase Phr1 regulates axon outgrowth through modulation of microtubule dynamics. Neuron 56 (2007) 604-620. The authors identify a mouse Phr1 mutant with error-prone motor axons that fail to exit choice points. Phr1 mutant axons display microtubule defects at the growth cone. Phr1 suppresses DLK level/p38 activity in axon shaft of motoneurons.
14. Bloom A.J., Miller B.R., Sanes J.R., and DiAntonio A. The requirement for Phr1 in CNS axon tract formation reveals the corticostriatal boundary as a choice point for cortical axons. Genes Dev 21 (2007) 2593-2606. This study focuses on the CNS defects of Phr1 mutants that are characterized by narrowing or total loss of axon tracts. Phr1 guides cortical axons through corticostriatal boundary partially through cell non-autonomous mechanisms, and axon defects are not dependent on DLK.
15. Park E.C., Glodowski D.R., and Rongo C. The ubiquitin ligase RPM-1 and the p38 MAPK PMK-3 regulate AMPA receptor trafficking. PLoS One 4 (2009) e4284. The authors describe a role for PHR proteins in postsynaptic development. Dependent on p38 MAPK, a RPM-1/FSN-1 E3 ligase affects the endosomal trafficking of GLR-1, an AMPA-type glutamate receptor at C. elegans interneuron synapses.
16. Garbarini N., and Delpire E. The RCC1 domain of protein associated with Myc (PAM) interacts with and regulates KCC2. Cell Physiol Biochem 22 (2008) 31-44
17. Li H., Khirug S., Cai C., Ludwig A., Blaesse P., Kolikova J., Afzalov R., Coleman S.K., Lauri S., Airaksinen M.S., et al. KCC2 interacts with the dendritic cytoskeleton to promote spine development. Neuron 56 (2007) 1019-1033
18. Hendricks M., Mathuru A.S., Wang H., Silander O., Kee M.Z., and Jesuthasan S. Disruption of Esrom and Ryk identifies the roof plate boundary as an intermediate target for commissure formation. Mol Cell Neurosci 37 (2008) 271-283
19. Hendricks M., and Jesuthasan S. PHR regulates growth cone pausing at intermediate targets through microtubule disassembly. J Neurosci 29 (2009) 6593-6598. This study identifies a role for Esrom-regulated microtubule dynamics during axon crossing at the choice point at the zebrafish CNS. esrom defects do not result from aberrant p38 MAPK signaling.
20. DiAntonio A., Haghighi A.P., Portman S.L., Lee J.D., Amaranto A.M., and Goodman C.S. Ubiquitination-dependent mechanisms regulate synaptic growth and function. Nature 412 (2001) 449-452
21. Liao E.H., Hung W., Abrams B., and Zhen M. An SCF-like ubiquitin ligase complex that controls presynaptic differentiation. Nature 430 (2004) 345-350. This study identifies an F-box protein, FSN-1, as a functional partner of RPM-1 to regulate synapse formation. FSN-1 and RPM-1 form a novel E3 ubiquitin ligase complex. The authors further show that ALK levels are increased in fsn-1 mutants, and alk mutation partially suppresses synaptic defects in fsn-1 mutants.
22. Wu C., Daniels R.W., and DiAntonio A. DFsn collaborates with Highwire to down-regulate the Wallenda/DLK kinase and restrain synaptic terminal growth. Neural Dev 2 (2007) 16. This study demonstrates that Drosophila FSN-1, DFsn, forms an E3 ubiquitin ligase complex with HIW and functions together with HIW to negatively regulate Wallenda and synaptic growth.
23. Saiga T., Fukuda T., Matsumoto M., Tada H., Okano H.J., Okano H., and Nakayama K.I. Fbxo45 forms a novel ubiquitin ligase complex and is required for neuronal development. Mol Cell Biol 29 (2009) 3529-3543. A targeted knockout of Fbxo45, the mammalian homolog of FSN-1, exhibited similar phenotypes to Phr1 mutants. Fbxo45 and Phr1 form an E3 ubiquitin ligase complex that includes Skp1, but not Cullin. Instead, Fbxo45 and Phr1 interact directly via their SPRY and Myc-binding domains, respectively. There are no gross changes in protein levels for all predicted PHR or FSN-1 targets: DLK, TSC2 or ALK.
24. Tyers M., and Jorgensen P. Proteolysis and the cell cycle: with this RING I do thee destroy. Curr Opin Genet Dev 10 (2000) 54-64
25. Deshaies R.J. SCF and Cullin/Ring H2-based ubiquitin ligases. Annu Rev Cell Dev Biol 15 (1999) 435-467
26. Nakata K., Abrams B., Grill B., Goncharov A., Huang X., Chisholm A.D., and Jin Y. Regulation of a DLK-1 and p38 MAP kinase pathway by the ubiquitin ligase RPM-1 is required for presynaptic development. Cell 120 (2005) 407-420. The authors identify DLK-1 and DLK-mediated MAPK signaling as key targets of RPM 1-regulated ubiquitination and downregulation during synaptogenesis.
27. Grill B., Bienvenut W.V., Brown H.M., Ackley B.D., Quadroni M., and Jin Y. C. elegans RPM-1 regulates axon termination and synaptogenesis through the Rab GEF GLO-4 and the Rab GTPase GLO-1. Neuron 55 (2007) 587-601. This study identifies a biochemical and genetic interaction between RPM-1 and a guanine nucleotide exchange factor GLO-4. RPM-1 probably regulates endosomal trafficking in neurons through a GLO-4-dependent, E3-ligase independent, signaling pathway, to regulate axon termination.
28. Yan D., Wu Z., Chisholm A.D., and Jin Y. The DLK-1 kinase promotes mRNA stability and local translation in C. elegans synapses and axon regeneration. Cell 138 (2009) 1005-1018
29. Collins C.A., Wairkar Y.P., Johnson S.L., and DiAntonio A. Highwire restrains synaptic growth by attenuating a MAP kinase signal. Neuron 51 (2006) 57-69. The Drosophila DLK homolog, Wallenda, is downregulated by a HIW. However, Wallenda regulates synaptic growth through JNK and d-Fos transcription factor, not p38 signaling.
30. Murthy V., Han S., Beauchamp R.L., Smith N., Haddad L.A., Ito N., and Ramesh V. Pam and its ortholog highwire interact with and may negatively regulate the TSC1.TSC2 complex. J Biol Chem 279 (2004) 1351-1358. The authors show a physical association between the RING finger domain of Pam and TSC2/tuberin. Mutations in hiw enhance the small eye phenotype induced by ectopic expression of TSC1-TSC2, suggesting that HIW can downregulate the activity of TSC complex in vivo.
31. Han S., Witt R.M., Santos T.M., Polizzano C., Sabatini B.L., and Ramesh V. Pam (Protein associated with Myc) functions as an E3 ubiquitin ligase and regulates TSC/mTOR signaling. Cell Signal 20 (2008) 1084-1091
32. McCabe B.D., Hom S., Aberle H., Fetter R.D., Marques G., Haerry T.E., Wan H., O'Connor M.B., Goodman C.S., and Haghighi A.P. Highwire regulates presynaptic BMP signaling essential for synaptic growth. Neuron 41 (2004) 891-905. Highwire binds a co-Smad Medea. Moreover, reducing the activity of BMP signaling leads to reduced synaptic growth, and partially suppresses the excessive synaptic growth defects of hiw mutants, suggesting that BMP signaling contributes to abnormal NMJ morphology in hiw mutants.
33. Merino C., Penney J., Gonzalez M., Tsurudome K., Moujahidine M., O'Connor M.B., Verheyen E.M., and Haghighi P. Nemo kinase interacts with Mad to coordinate synaptic growth at the Drosophila neuromuscular junction. J Cell Biol 185 (2009) 713-725
34. Scholich K., Pierre S., and Patel T.B. Protein associated with Myc (PAM) is a potent inhibitor of adenylyl cyclases. J Biol Chem 276 (2001) 47583-47589
35. Pierre S., Maeurer C., Coste O., Becker W., Schmidtko A., Holland S., Wittpoth C., Geisslinger G., and Scholich K. Toponomics analysis of functional interactions of the ubiquitin ligase PAM (Protein Associated with Myc) during spinal nociceptive processing. Mol Cell Proteomics 7 (2008) 2475-2485
36. Miller B.R., Press C., Daniels R.W., Sasaki Y., Milbrandt J., and DiAntonio A. A dual leucine kinase-dependent axon self-destruction program promotes Wallerian degeneration. Nat Neurosci 12 (2009) 387-389. This study demonstrates that Wallenda and DLK are required for the activation of Wallerian degeneration after axotomy in Drosophila and mouse neurons.
37. Horiuchi D., Collins C.A., Bhat P., Barkus R.V., Diantonio A., and Saxton W.M. Control of a kinesin-cargo linkage mechanism by JNK pathway kinases. Curr Biol 17 (2007) 1313-1317
38. Le Guyader S., Maier J., and Jesuthasan S. Esrom, an ortholog of PAM (protein associated with c-myc), regulates pteridine synthesis in the zebrafish. Dev Biol 277 (2005) 378-386. This study describes a non-neural role for PHR proteins. esrom mutants have a pigment defect owing to the reduction in the synthesis of pteridine.
39. Odenthal J., Rossnagel K., Haffter P., Kelsh R.N., Vogelsang E., Brand M., van Eeden F.J., Furutani-Seiki M., Granato M., Hammerschmidt M., et al. Mutations affecting xanthophore pigmentation in the zebrafish, Danio rerio. Development 123 (1996) 391-398
40. Gao M.X., Liao E.H., Yu B., Wang Y., Zhen M., and Derry W.B. The SCF FSN-1 ubiquitin ligase controls germline apoptosis through CEP-1/p53 in C. elegans. Cell Death Differ 15 (2008) 1054-1062. An E3 ubiquitin ligase composed of FSN-1 and RPM-1 regulates ENU-induced apopotosis in C. elegans germline by downregulating phosphorylated CEP-1/p53, an activator of apoptosis.
41. Peschiaroli A., Scialpi F., Bernassola F., Pagano M., and Melino G. The F-box protein FBXO45 promotes the proteasome-dependent degradation of p73. Oncogene (2009)