The Nesprin Family Member ANC-1 Regulates Synapse Formation and Axon Termination by Functioning in a Pathway with RPM-1 and β-Catenin
The molecular mechanisms that underpin synapse formation and axon termination are central to forming a functional, fully connected nervous system. The PHR proteins are important regulators of neuronal development that function in axon outgrowth and termination, as well as synapse formation. Here we describe the discovery of a novel, conserved pathway that is positively regulated by the C. elegans PHR protein, RPM-1. This pathway is composed of RPM-1, ANC-1 (a Nesprin family protein), and BAR-1 (a canonical β-catenin). Nesprins, such as ANC-1, regulate nuclear anchorage and positioning in multinuclear cells. We now show that in neurons, ANC-1 regulates neuronal development by positively regulating BAR-1. Thus, Nesprins are multi-functional proteins that act through β-catenin to regulate neuronal development, and link the nucleus to the actin cytoskeleton in order to mediate nuclear anchorage and positioning in multi-nuclear cells.
Vyšlo v časopise:
The Nesprin Family Member ANC-1 Regulates Synapse Formation and Axon Termination by Functioning in a Pathway with RPM-1 and β-Catenin. PLoS Genet 10(7): e32767. doi:10.1371/journal.pgen.1004481
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1004481
Souhrn
The molecular mechanisms that underpin synapse formation and axon termination are central to forming a functional, fully connected nervous system. The PHR proteins are important regulators of neuronal development that function in axon outgrowth and termination, as well as synapse formation. Here we describe the discovery of a novel, conserved pathway that is positively regulated by the C. elegans PHR protein, RPM-1. This pathway is composed of RPM-1, ANC-1 (a Nesprin family protein), and BAR-1 (a canonical β-catenin). Nesprins, such as ANC-1, regulate nuclear anchorage and positioning in multinuclear cells. We now show that in neurons, ANC-1 regulates neuronal development by positively regulating BAR-1. Thus, Nesprins are multi-functional proteins that act through β-catenin to regulate neuronal development, and link the nucleus to the actin cytoskeleton in order to mediate nuclear anchorage and positioning in multi-nuclear cells.
Zdroje
1. StarrDA, FridolfssonHN (2010) Interactions between nuclei and the cytoskeleton are mediated by SUN-KASH nuclear-envelope bridges. Annu Rev Cell Dev Biol 26: 421–444.
2. ZhangX, XuR, ZhuB, YangX, DingX, et al. (2007) Syne-1 and Syne-2 play crucial roles in myonuclear anchorage and motor neuron innervation. Development 134: 901–908.
3. LuxtonGW, GomesER, FolkerES, VintinnerE, GundersenGG (2010) Linear arrays of nuclear envelope proteins harness retrograde actin flow for nuclear movement. Science 329: 956–959.
4. ZhangX, LeiK, YuanX, WuX, ZhuangY, et al. (2009) SUN1/2 and Syne/Nesprin-1/2 complexes connect centrosome to the nucleus during neurogenesis and neuronal migration in mice. Neuron 64: 173–187.
5. Elhanany-TamirH, YuYV, ShnayderM, JainA, WelteM, et al. (2012) Organelle positioning in muscles requires cooperation between two KASH proteins and microtubules. J Cell Biol 198: 833–846.
6. StarrDA, HanM (2002) Role of ANC-1 in tethering nuclei to the actin cytoskeleton. Science 298: 406–409.
7. GoughLL, BeckKA (2004) The spectrin family member Syne-1 functions in retrograde transport from Golgi to ER. Biochim Biophys Acta 1693: 29–36.
8. YuTW, ChahrourMH, CoulterME, JiralerspongS, Okamura-IkedaK, et al. (2013) Using Whole-Exome Sequencing to Identify Inherited Causes of Autism. Neuron 77: 259–273.
9. O'RoakBJ, DeriziotisP, LeeC, VivesL, SchwartzJJ, et al. (2011) Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat Genet 43: 585–589.
10. Gros-LouisF, DupreN, DionP, FoxMA, LaurentS, et al. (2007) Mutations in SYNE1 lead to a newly discovered form of autosomal recessive cerebellar ataxia. Nat Genet 39: 80–85.
11. ZhangQ, BethmannC, WorthNF, DaviesJD, WasnerC, et al. (2007) Nesprin-1 and -2 are involved in the pathogenesis of Emery Dreifuss muscular dystrophy and are critical for nuclear envelope integrity. Hum Mol Genet 16: 2816–2833.
12. TessemaM, WillinkR, DoK, YuYY, YuW, et al. (2008) Promoter methylation of genes in and around the candidate lung cancer susceptibility locus 6q23-25. Cancer Res 68: 1707–1714.
13. AttaliR, WarwarN, IsraelA, GurtI, McNallyE, et al. (2009) Mutation of SYNE-1, encoding an essential component of the nuclear lamina, is responsible for autosomal recessive arthrogryposis. Hum Mol Genet 18: 3462–3469.
14. PuckelwartzMJ, KesslerEJ, KimG, DewittMM, ZhangY, et al. (2010) Nesprin-1 mutations in human and murine cardiomyopathy. J Mol Cell Cardiol 48: 600–608.
15. AndreassenOA, ThompsonWK, SchorkAJ, RipkeS, MattingsdalM, et al. (2013) Improved detection of common variants associated with schizophrenia and bipolar disorder using pleiotropy-informed conditional false discovery rate. PLoS Genet 9: e1003455.
16. GreenEK, GrozevaD, FortyL, Gordon-SmithK, RussellE, et al. (2013) Association at SYNE1 in both bipolar disorder and recurrent major depression. Mol Psychiatry 18: 614–617.
17. SklarP, RipkeS, ScottLJ, AndreassenOA, CichonS, CraddockN, EdenbergHJ, NurnbergerJI, RietschelM, BlackwoodD (2011) Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nat Genet 43: 977–983.
18. ApelED, LewisRM, GradyRM, SanesJR (2000) Syne-1, a dystrophin- and Klarsicht-related protein associated with synaptic nuclei at the neuromuscular junction. J Biol Chem 275: 31986–31995.
19. GradyRM, StarrDA, AckermanGL, SanesJR, HanM (2005) Syne proteins anchor muscle nuclei at the neuromuscular junction. Proc Natl Acad Sci U S A 102: 4359–4364.
20. Del BeneF, WehmanAM, LinkBA, BaierH (2008) Regulation of neurogenesis by interkinetic nuclear migration through an apical-basal notch gradient. Cell 134: 1055–1065.
21. LeinES, HawrylyczMJ, AoN, AyresM, BensingerA, et al. (2007) Genome-wide atlas of gene expression in the adult mouse brain. Nature 445: 168–176.
22. CottrellJR, BorokE, HorvathTL, NediviE (2004) CPG2: a brain- and synapse-specific protein that regulates the endocytosis of glutamate receptors. Neuron 44: 677–690.
23. WarrenDT, TajsicT, MelladJA, SearlesR, ZhangQ, et al. (2010) Novel nuclear nesprin-2 variants tether active extracellular signal-regulated MAPK1 and MAPK2 at promyelocytic leukemia protein nuclear bodies and act to regulate smooth muscle cell proliferation. J Biol Chem 285: 1311–1320.
24. NeumannS, SchneiderM, DaughertyRL, GottardiCJ, EmingSA, et al. (2010) Nesprin-2 interacts with {alpha}-catenin and regulates Wnt signaling at the nuclear envelope. J Biol Chem 285: 34932–34938.
25. PoMD, HwangC, ZhenM (2010) PHRs: bridging axon guidance, outgrowth and synapse development. Curr Opin Neurobiol 20: 100–107.
26. LewcockJW, GenoudN, LettieriK, PfaffSL (2007) The ubiquitin ligase Phr1 regulates axon outgrowth through modulation of microtubule dynamics. Neuron 56: 604–620.
27. SchaeferAM, HadwigerGD, NonetML (2000) rpm-1, a conserved neuronal gene that regulates targeting and synaptogenesis in C. elegans. Neuron 26: 345–356.
28. KimJH, WangX, CoolonR, YeB (2013) Dscam expression levels determine presynaptic arbor sizes in Drosophila sensory neurons. Neuron 78: 827–838.
29. LiH, KulkarniG, WadsworthWG (2008) 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: 3595–3603.
30. BloomAJ, MillerBR, SanesJR, DiAntonioA (2007) The requirement for Phr1 in CNS axon tract formation reveals the corticostriatal boundary as a choice point for cortical axons. Genes Dev 21: 2593–2606.
31. D'SouzaJ, HendricksM, Le GuyaderS, SubburajuS, GrunewaldB, et al. (2005) Formation of the retinotectal projection requires Esrom, an ortholog of PAM (protein associated with Myc). Development 132: 247–256.
32. ZhenM, HuangX, BamberB, JinY (2000) Regulation of presynaptic terminal organization by C. elegans RPM-1, a putative guanine nucleotide exchanger with a RING-H2 finger domain. Neuron 26: 331–343.
33. BurgessRW, PetersonKA, JohnsonMJ, RoixJJ, WelshIC, et al. (2004) Evidence for a conserved function in synapse formation reveals Phr1 as a candidate gene for respiratory failure in newborn mice. Mol Cell Biol 24: 1096–1105.
34. WanHI, DiAntonioA, FetterRD, BergstromK, StraussR, et al. (2000) Highwire regulates synaptic growth in Drosophila. Neuron 26: 313–329.
35. XiongX, WangX, EwanekR, BhatP, DiantonioA, et al. (2010) Protein turnover of the Wallenda/DLK kinase regulates a retrograde response to axonal injury. J Cell Biol 191: 211–223.
36. HammarlundM, NixP, HauthL, JorgensenEM, BastianiM (2009) Axon regeneration requires a conserved MAP kinase pathway. Science 323: 802–806.
37. XiongX, HaoY, SunK, LiJ, LiX, et al. (2012) The Highwire ubiquitin ligase promotes axonal degeneration by tuning levels of Nmnat protein. PLoS Biol 10: e1001440.
38. BabettoE, BeirowskiB, RusslerEV, MilbrandtJ, DiAntonioA (2013) The Phr1 ubiquitin ligase promotes injury-induced axon self-destruction. Cell Rep 3: 1422–1429.
39. NakataK, AbramsB, GrillB, GoncharovA, HuangX, et al. (2005) Regulation of a DLK-1 and p38 MAP kinase pathway by the ubiquitin ligase RPM-1 is required for presynaptic development. Cell 120: 407–420.
40. CollinsCA, WairkarYP, JohnsonSL, DiantonioA (2006) Highwire Restrains Synaptic Growth by Attenuating a MAP Kinase Signal. Neuron 51: 57–69.
41. MurthyV, HanS, BeauchampRL, SmithN, HaddadLA, et al. (2004) Pam and its ortholog highwire interact with and may negatively regulate the TSC1.TSC2 complex. J Biol Chem 279: 1351–1358.
42. GrillB, BienvenutWV, BrownHM, AckleyBD, QuadroniM, et al. (2007) C. elegans RPM-1 Regulates Axon Termination and Synaptogenesis through the Rab GEF GLO-4 and the Rab GTPase GLO-1. Neuron 55: 587–601.
43. GrillB, ChenL, TulgrenED, BakerST, BienvenutW, et al. (2012) RAE-1, a Novel PHR Binding Protein, Is Required for Axon Termination and Synapse Formation in Caenorhabditis elegans. J Neurosci 32: 2628–2636.
44. TianX, LiJ, ValakhV, DiAntonioA, WuC (2011) Drosophila Rae1 controls the abundance of the ubiquitin ligase Highwire in post-mitotic neurons. Nat Neurosci 14: 1267–1275.
45. LiaoEH, HungW, AbramsB, ZhenM (2004) An SCF-like ubiquitin ligase complex that controls presynaptic differentiation. Nature 430: 345–350.
46. McCabeBD, HomS, AberleH, FetterRD, MarquesG, et al. (2004) Highwire regulates presynaptic BMP signaling essential for synaptic growth. Neuron 41: 891–905.
47. BakerST, OppermanKJ, TulgrenED, TurgeonSM, BienvenutW, et al. (2014) RPM-1 Uses Both Ubiquitin Ligase and Phosphatase-Based Mechanisms to Regulate DLK-1 during Neuronal Development. PLoS Genet 10: e1004297.
48. HallamSJ, JinY (1998) lin-14 regulates the timing of synaptic remodelling in Caenorhabditis elegans. Nature 395: 78–82.
49. HungWL, HwangC, GaoS, LiaoEH, ChitturiJ, et al. (2013) Attenuation of insulin signalling contributes to FSN-1-mediated regulation of synapse development. EMBO J 32: 1745–1760.
50. YochemJ, GuT, HanM (1998) A new marker for mosaic analysis in Caenorhabditis elegans indicates a fusion between hyp6 and hyp7, two major components of the hypodermis. Genetics 149: 1323–1334.
51. CleversH, NusseR (2012) Wnt/beta-catenin signaling and disease. Cell 149: 1192–1205.
52. KirszenblatL, PattabiramanD, HilliardMA (2011) LIN-44/Wnt directs dendrite outgrowth through LIN-17/Frizzled in C. elegans Neurons. PLoS Biol 9: e1001157.
53. PanCL, HowellJE, ClarkSG, HilliardM, CordesS, et al. (2006) Multiple Wnts and frizzled receptors regulate anteriorly directed cell and growth cone migrations in Caenorhabditis elegans. Dev Cell 10: 367–377.
54. PrasadBC, ClarkSG (2006) Wnt signaling establishes anteroposterior neuronal polarity and requires retromer in C. elegans. Development 133: 1757–1766.
55. DreierL, BurbeaM, KaplanJM (2005) LIN-23-mediated degradation of beta-catenin regulates the abundance of GLR-1 glutamate receptors in the ventral nerve cord of C. elegans. Neuron 46: 51–64.
56. MehtaN, LoriaPM, HobertO (2004) A genetic screen for neurite outgrowth mutants in Caenorhabditis elegans reveals a new function for the F-box ubiquitin ligase component LIN-23. Genetics 166: 1253–1267.
57. ParkEC, GlodowskiDR, RongoC (2009) The ubiquitin ligase RPM-1 and the p38 MAPK PMK-3 regulate AMPA receptor trafficking. PLoS One 4: e4284.
58. JacksonBM, EisenmannDM (2012) beta-catenin-dependent Wnt signaling in C. elegans: teaching an old dog a new trick. Cold Spring Harb Perspect Biol 4: a007948.
59. PhillipsBT, KimbleJ (2009) A new look at TCF and beta-catenin through the lens of a divergent C. elegans Wnt pathway. Dev Cell 17: 27–34.
60. KorswagenHC, HermanMA, CleversHC (2000) Distinct beta-catenins mediate adhesion and signalling functions in C. elegans. Nature 406: 527–532.
61. EisenmannDM, MaloofJN, SimskeJS, KenyonC, KimSK (1998) The beta-catenin homolog BAR-1 and LET-60 Ras coordinately regulate the Hox gene lin-39 during Caenorhabditis elegans vulval development. Development 125: 3667–3680.
62. VashlishanAB, MadisonJM, DybbsM, BaiJ, SieburthD, et al. (2008) An RNAi screen identifies genes that regulate GABA synapses. Neuron 58: 346–361.
63. SiegfriedKR, KimbleJ (2002) POP-1 controls axis formation during early gonadogenesis in C. elegans. Development 129: 443–453.
64. ChalfieM, ThomsonJN (1979) Organization of neuronal microtubules in the nematode Caenorhabditis elegans. J Cell Biol 82: 278–289.
65. Ch'ngQ, WilliamsL, LieYS, SymM, WhangboJ, et al. (2003) Identification of genes that regulate a left-right asymmetric neuronal migration in Caenorhabditis elegans. Genetics 164: 1355–1367.
66. RocheleauCE, DownsWD, LinR, WittmannC, BeiY, et al. (1997) Wnt signaling and an APC-related gene specify endoderm in early C. elegans embryos. Cell 90: 707–716.
67. KorswagenHC, CoudreuseDY, BetistMC, van de WaterS, ZivkovicD, et al. (2002) The Axin-like protein PRY-1 is a negative regulator of a canonical Wnt pathway in C. elegans. Genes Dev 16: 1291–1302.
68. MaloneCJ, FixsenWD, HorvitzHR, HanM (1999) UNC-84 localizes to the nuclear envelope and is required for nuclear migration and anchoring during C. elegans development. Development 126: 3171–3181.
69. MarkiewiczE, TilgnerK, BarkerN, van de WeteringM, CleversH, et al. (2006) The inner nuclear membrane protein emerin regulates beta-catenin activity by restricting its accumulation in the nucleus. EMBO J 25: 3275–3285.
70. ZhangQ, RagnauthCD, SkepperJN, WorthNF, WarrenDT, et al. (2005) Nesprin-2 is a multi-isomeric protein that binds lamin and emerin at the nuclear envelope and forms a subcellular network in skeletal muscle. J Cell Sci 118: 673–687.
71. LibotteT, ZaimH, AbrahamS, PadmakumarVC, SchneiderM, et al. (2005) Lamin A/C-dependent localization of Nesprin-2, a giant scaffolder at the nuclear envelope. Mol Biol Cell 16: 3411–3424.
72. HaithcockE, DayaniY, NeufeldE, ZahandAJ, FeinsteinN, et al. (2005) Age-related changes of nuclear architecture in Caenorhabditis elegans. Proc Natl Acad Sci U S A 102: 16690–16695.
73. HilliardMA, BargmannCI (2006) Wnt signals and frizzled activity orient anterior-posterior axon outgrowth in C. elegans. Dev Cell 10: 379–390.
74. HarterinkM, KimDH, MiddelkoopTC, DoanTD, van OudenaardenA, et al. (2011) Neuroblast migration along the anteroposterior axis of C. elegans is controlled by opposing gradients of Wnts and a secreted Frizzled-related protein. Development 138: 2915–2924.
75. MaroGS, KlassenMP, ShenK (2009) A beta-catenin-dependent Wnt pathway mediates anteroposterior axon guidance in C. elegans motor neurons. PLoS One 4: e4690.
76. KiddAR3rd, MiskowskiJA, SiegfriedKR, SawaH, KimbleJ (2005) A beta-catenin identified by functional rather than sequence criteria and its role in Wnt/MAPK signaling. Cell 121: 761–772.
77. LoMC, GayF, OdomR, ShiY, LinR (2004) Phosphorylation by the beta-catenin/MAPK complex promotes 14-3-3-mediated nuclear export of TCF/POP-1 in signal-responsive cells in C. elegans. Cell 117: 95–106.
78. ZechnerD, FujitaY, HulskenJ, MullerT, WaltherI, et al. (2003) beta-Catenin signals regulate cell growth and the balance between progenitor cell expansion and differentiation in the nervous system. Dev Biol 258: 406–418.
79. BamjiSX, ShimazuK, KimesN, HuelskenJ, BirchmeierW, et al. (2003) Role of beta-catenin in synaptic vesicle localization and presynaptic assembly. Neuron 40: 719–731.
80. YuX, MalenkaRC (2003) Beta-catenin is critical for dendritic morphogenesis. Nat Neurosci 6: 1169–1177.
81. MuraseS, MosserE, SchumanEM (2002) Depolarization drives beta-Catenin into neuronal spines promoting changes in synaptic structure and function. Neuron 35: 91–105.
82. VotinV, NelsonWJ, BarthAI (2005) Neurite outgrowth involves adenomatous polyposis coli protein and beta-catenin. J Cell Sci 118: 5699–5708.
83. ElulTM, KimesNE, KohwiM, ReichardtLF (2003) N- and C-terminal domains of beta-catenin, respectively, are required to initiate and shape axon arbors of retinal ganglion cells in vivo. J Neurosci 23: 6567–6575.
84. LiXM, DongXP, LuoSW, ZhangB, LeeDH, et al. (2008) Retrograde regulation of motoneuron differentiation by muscle beta-catenin. Nat Neurosci 11: 262–268.
85. AbramsB, GrillB, HuangX, JinY (2008) Cellular and molecular determinants targeting the Caenorhabditis elegans PHR protein RPM-1 to perisynaptic regions. Dev Dyn 237: 630–639.
86. EhnertC, TegederI, PierreS, BirodK, NguyenHV, et al. (2004) Protein associated with Myc (PAM) is involved in spinal nociceptive processing. J Neurochem 88: 948–957.
87. SantosTM, HanS, BowserM, SazaniK, BeauchampRL, et al. (2006) Alternative splicing in protein associated with Myc (Pam) influences its binding to c-Myc. J Neurosci Res 83: 222–232.
88. ShenK, CowanCW (2010) Guidance molecules in synapse formation and plasticity. Cold Spring Harb Perspect Biol 2: a001842.
89. HendricksM, MathuruAS, WangH, SilanderO, KeeMZ, et al. (2008) Disruption of Esrom and Ryk identifies the roof plate boundary as an intermediate target for commissure formation. Mol Cell Neurosci 37: 271–283.
90. KennerdellJR, FetterRD, BargmannCI (2009) Wnt-Ror signaling to SIA and SIB neurons directs anterior axon guidance and nerve ring placement in C. elegans. Development 136: 3801–3810.
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Genetika Reprodukčná medicínaČlánok vyšiel v časopise
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