TRIM Proteins in Development

  • Francesca Petrera
  • Germana Meroni
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 770)


TRIM proteins play important roles in several patho-physiological processes. Their common activity within the ubiquity lation pathway makes them amenable to a number of diverse biological roles. Many of the TRIM genes are highly and sometimes specifically expressed during embryogenesis, it is therefore not surprising that several of them might be involved in developmental processes. Here, we primarily discuss the developmental implications of two subgroups of TRIM proteins that conserved domain composition and functions from their invertebrate ancestors. The two groups are: the TRIM-NHL proteins implicated in miRNA processing regulation and the TRIM-FN3 proteins involved in ventral midline development.


Neural Tube Closure Cell Cycle Exit Tripartite Motif Synaptic Vesicle Exocytosis Trim Gene 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Reymond A, Meroni G, Fantozzi A et al. The tripartite motif family identifies cell compartments. EMBO J 2001; 20(9):2140–2151.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Sardiello M, Cairo S, Fontaneila B et al. Genomic analysis of the TRIM family reveals two groups of genes with distinct evolutionary properties. BMC Evol Biol 2008; 8:225.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Short KM, Cox TC. Sub-classification of the rbcc/trim superfamily reveals a novel motif necessary for microtubule binding. J Biol Chem 2006.Google Scholar
  4. 4.
    Slack FJ, Ruvkun G. A novel repeat domain that is often associated with RING finger and B-box motifs. Trends Biochem Sci 1998; 23(12):474–475.PubMedCrossRefGoogle Scholar
  5. 5.
    Edwards TA, Wilkinson BD, Wharton RP et al. Model of the brain tumor-Pumilio translation repressor complex. Genes Dev 2003; 17(20):2508–2513.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    El-Husseini AE, Vincent SR. Cloning and characterization of a novel RING finger protein that interacts with class V myosins. J Biol Chem 1999; 274(28): 19771–19777.PubMedCrossRefGoogle Scholar
  7. 7.
    Ohkawa N, Kokura K, Matsu-Ura T et al. Molecular cloning and characterization of neural activity-related RING finger protein (NARF): a new member of the RBCC family is a candidate for the partner of myosin V. J Neurochem 2001; 78(1):75–87.PubMedCrossRefGoogle Scholar
  8. 8.
    Yan Q, Sun W, Kujala P et al. CART: an Hrs/actinin-4/BERP/myosin V protein complex required for efficient receptor recycling. Mol Biol Cell 2005; 16(5):2470–2482.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Balastik M, Ferraguti F, Pires-da Silva A et al. Deficiency in ubiquitin ligase TRIM2 causes accumulation of neurofilament light chain and neurodegeneration. Proc Natl Acad Sci USA 2008; 105(33): 12016–12021.PubMedCrossRefGoogle Scholar
  10. 10.
    Frosk P, Weiler T, Nylen E et al. Limb-girdle muscular dystrophy type 2H associated with mutation in TRIM32, a putative E3-ubiquitin-ligase gene. Am J Hum Genet 2002; 70(3):663–672.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Chiang AP, Beck JS, Yen HJ et al. Homozygosity mapping with SNP arrays identifies TRIM32, an E3 ubiquitin ligase, as a Bardet-Bied1 syndrome gene (BBS11). Proc Natl Acad Sci USA 2006; 103(16):6287–6292.PubMedCrossRefGoogle Scholar
  12. 12.
    Kudryashova E, Struyk A, Mokhonova E et al. The common missense mutation D489N in TRIM32 causing limb girdle muscular dystrophy 2H leads to loss of the mutated protein in knock-in mice resulting in a Trim32-null phenotype. Hum Mol Genet 2011; 20(20):3925–3932.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Kudryashova E, Wu J, Havton LA et al. Deficiency of the E3 ubiquitin ligase TRIM32 in mice leads to a myopathy with a neurogenic component. Hum Mol Genet 2009; 18(7):1353–1367.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Schwamborn JC, Berezikov E, Knoblich JA. The TRIM-NHL protein TRIM32 activates microRNAs and prevents self-renewal in mouse neural progenitors. Cell 2009; 136(5):913–925.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Albor A, El-Hizawi S, Horn EJ et al. The interaction of Piasy with Trim32, an E3-ubiquitin ligase mutated in limb-girdle muscular dystrophy type 2H, promotes Piasy degradation and regulates UVB-induced keratinocyte apoptosis through NFkappaB. J Biol Chem 2006; 281(35):25850–25866.PubMedCrossRefGoogle Scholar
  16. 16.
    Kano S, Miyajima N, Fukuda S et al. Tripartite motif protein 32 facilitates cell growth and migration via degradation of Abl-interactor 2. Cancer Res 2008; 68(14):5572–5580.PubMedCrossRefGoogle Scholar
  17. 17.
    Kudryashova E, Kudryashov D, Kramerova I et al. Trim32 is a ubiquitin ligase mutated in limb girdle muscular dystrophy type 2H that binds to skeletal muscle myosin and ubiquitinates actin. J Mol Biol 2005; 354(2):413–424.PubMedCrossRefGoogle Scholar
  18. 18.
    Liu Y, Lagowski JP, Gao S et al. Regulation of the psoriatic chemokine CCL20 by E3 ligases Trim32 and Piasy in keratinocytes. J Invest Dermatol 2010; 130(5):1384–1390.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Sato T, Okumura F, Kano S et al. TRIM32 promotes neural differentiation through retinoic acid receptor-mediated transcription. J Cell Sci 2011; 124(Pt 20):3492–3502.PubMedCrossRefGoogle Scholar
  20. 20.
    Slack FJ, Basson M, Liu Z et al. The lin-41 RBCC gene acts in the C. elegans heterochronic pathway between the let-7 regulatory RNA and the LIN-29 transcription factor. Mol Cell 2000; 5(4):659–669.PubMedCrossRefGoogle Scholar
  21. 21.
    Schulman BR, Esquela-Kerscher A, Slack FJ. Reciprocal expression of lin-41 and the microRNAs let-7 and mir-125 during mouse embryogenesis. Dev Dyn 2005; 234(4): 1046–1054.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Kanamoto T, Terada K, Yoshikawa H et al. Cloning and regulation of the vertebrate homologue of lin-41 that functions as a heterochronic gene in Caenorhabditis elegans. Dev Dyn 2006; 235(4): 1142–1149.PubMedCrossRefGoogle Scholar
  23. 23.
    Mailer Schulman BR, Liang X, Stahlhut C et al. The let-7 microRNA target gene, Mlin41/Trim71 is required for mouse embryonic survival and neural tube closure. Cell Cycle 2008; 7(24):3935–3942.CrossRefGoogle Scholar
  24. 24.
    Loer B, Bauer R, Bornheim R et al. The NHL-domain protein Wech is crucial forthe integrin-cytoskeleton link. Nat Cell Biol 2008; 10(4):422–428.PubMedCrossRefGoogle Scholar
  25. 25.
    Arama E, Dickman D, Kimchie Z et al. Mutations in the beta-propeller domain of the Drosophila brain tumor (brat) protein induce neoplasm in the larval brain. Oncogene 2000; 19(33):3706–3716.PubMedCrossRefGoogle Scholar
  26. 26.
    Bello B, Reichert H, Hirth F. The brain tumor gene negatively regulates neural progenitor cell proliferation in the larval central brain of Drosophila. Development 2006; 133(14):2639–2648.PubMedCrossRefGoogle Scholar
  27. 27.
    Neumuller RA, Betschinger J, Fischer A et al. Mei-P26 regulates microRNAs and cell growth in the Drosophila ovarian stem cell lineage. Nature 2008; 454(7201):241–245.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Betschinger J, Mechtler K, Knoblich JA. Asymmetric segregation of the tumor suppressor brat regulates self-renewal in Drosophila neural stem cells. Cell 2006; 124(6):1241–1253.PubMedCrossRefGoogle Scholar
  29. 29.
    Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004; 116(2):281–297.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Hammell CM, Lubin I, Boag PR et al. nhl-2 Modulates microRNA activity in Caenorhabditis elegans. Cell 2009; 136(5):926–938.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Rybak A, Fuchs H, Hadian K et al. The let-7 target gene mouse lin-41 is a stem cell specific E3 ubiquitin ligase for the miRNA pathway protein Ago2. Nat Cell Biol 2009; 11(12): 1411–1420.PubMedCrossRefGoogle Scholar
  32. 32.
    Loedige I, Filipowicz W. TRIM-NHL proteins take on miRNA regulation. Cell 2009; 136(5):818–820.PubMedCrossRefGoogle Scholar
  33. 33.
    Cuykendall TN, Houston DW. Vegetally localized Xenopus trim36 regulates cortical rotation and dorsal axis formation. Development 2009; 136(18):3057–3065.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Quaderi NA, Schweiger S, Gaudenz K et al. Opitz G/BBB syndrome, a defect of midline development, is due to mutations in a new RING finger gene on Xp22. Nature Genetics 1997; 17:285–291.PubMedCrossRefGoogle Scholar
  35. 35.
    Fontaneila B, Russolillo G, Meroni G. MID1 mutations in patients with X-linked Opitz G/BBB syndrome. Hum Mutat 2008; 29(5):584–594.CrossRefGoogle Scholar
  36. 36.
    Lancioni A, Pizzo M, Fontaneila B et al. Lack of Mid1, the mouse ortholog of the Opitz syndrome gene, causes abnormal development of the anterior cerebellar vermis. J Neurosci 2010; 30(8):2880–2887.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Trockenbacher A, Suckow V, Foerster J et al. MID1, mutated in Opitz syndrome, encodes an ubiquitin ligase that targets phosphatase 2A for degradation. Nat Genet 2001; 29(3):287–294.PubMedCrossRefGoogle Scholar
  38. 38.
    Liu E, Knutzen CA, Krauss S et al. Control of mTORC1 signaling by the Opitz syndrome protein MID1. Proc Natl Acad Sci USA 2011; 108(21):8680–8685.PubMedCrossRefGoogle Scholar
  39. 39.
    Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 2011; 12(1):21–35.PubMedCrossRefGoogle Scholar
  40. 40.
    Aranda-Orgilles B, Rutschow D, Zeller R et al. Protein Phosphatase 2A (PP2A)-specific Ubiquitin Ligase MIDI Is a Sequence-dependent Regulator of Translation Efficiency Controlling 3-Phosphoinositide-dependent Protein Kinase-1 (PDPK-1). J Biol Chem 2011; 286(46):39945–39957.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Short KM, Hopwood B, Yi Z et al. MID1 and MID2 homo- and heterodimerise to tether the rapamycin-sensitive PP2A regulatory subunit, Alpha 4, to microtubules: implications for the clinical variability of X-linked Opitz GBBB syndrome and other developmental disorders. BMC Cell Biol 2002; 3(1): 1.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Buchner G, Montini E, Andolfi G et al. MID2, a homologue of the Opitz syndrome gene MID1: similarities in subcellular localization and differences in expression during development. Hum Mol Genet 1999; 8(8): 1397–1407.PubMedCrossRefGoogle Scholar
  43. 43.
    Granata A, Savery D, Hazan J et al. Evidence offunctional redundancy between MID proteins: implications for the presentation of Opitz syndrome. Dev Biol 2005; 277(2):417–424.PubMedCrossRefGoogle Scholar
  44. 44.
    Suzuki M, Hara Y, Takagi C et al. MID1 and MID2 are required for Xenopus neural tube closure through the regulation of microtubule organization. Development 2010; 137(14):2329–2339.PubMedCrossRefGoogle Scholar
  45. 45.
    Hao JC, Adler CE, Mebane L et al. The tripartite motif protein MADD-2 functions with the receptor UNC-40 (DCC) in Netrin-mediated axon attraction and branching. Dev Cell 2010; 18(6):950–960.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Alexander M, Selman G, Seetharaman A et al. MADD-2, a homolog of the Opitz syndrome protein MID1, regulates guidance to the midline through UNC-40 in Caenorhabditis elegans. Dev Cell 2010; 18(6):961–972.PubMedCrossRefGoogle Scholar
  47. 47.
    Morikawa RK, Kanamori T, Yasunaga K et al. Different levels of the Tripartite motif protein, Anomalies in sensory axon patterning (Asap), regulate distinct axonal projections of Drosophila sensory neurons. Proc Natl Acad Sci USA 2011; 108(48):19389–19394.PubMedCrossRefGoogle Scholar
  48. 48.
    Berti C, Messali S, Ballabio A et al. TRIM9 is specifically expressed in the embryonic and adult nervous system. Mech Dev 2002; 113(2): 159–162.PubMedCrossRefGoogle Scholar
  49. 49.
    Li Y, Chin LS, Weigel C et al. Spring, a novel RING finger protein that regulates synaptic vesicle exocytosis. J Biol Chem 2001; 276(44):40824–40833.PubMedCrossRefGoogle Scholar
  50. 50.
    Tanji K, Kamitani T, Mori F et al. TRIM9, a novel brain-specific E3 ubiquitin ligase, is repressed in the brain of Parkinson’s disease and dementia with Lewy bodies. Neurobiol Dis 2010; 38(2):210–218.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Simpson TI, Price DJ. Pax6; apleiotropic player in development. Bioessays 2002; 24(11):1041–1051.PubMedCrossRefGoogle Scholar
  52. 52.
    Tuoc TC, Stoykova A. Trim11 modulates the function of neurogenic transcription factor Pax6 through ubiquitin-proteosome system. Genes Dev 2008; 22(14): 1972–1986.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Schmierer B, Hill CS. TGFbeta-SMAD signal transduction: molecular specificity and functional flexibility. Nat Rev Mol Cell Biol 2007; 8(12):970–982.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    He W, Dorn DC, Erdjument-Bromage H. et al. Hematopoiesis controlled by distinct TIFlgamma and Smad4 branches of the TGFbeta pathway. Cell 2006; 125(5):929–941.PubMedCrossRefGoogle Scholar
  55. 55.
    Ransom DG, Bahary N, Niss K et al. The zebrafish moonshine gene encodes transcriptional intermediary factor lgamma, an essential regulator of hematopoiesis. PLoS Biol 2004; 2(8):E237.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Dupont S, Zacchigna L, Cordenonsi M et al. Germ-layer specification and control of cell growth by Ectodermin, a Smad4 ubiquitin ligase. Cell 2005; 121(1):87–99.PubMedCrossRefGoogle Scholar
  57. 57.
    Morsut L, Yan KP, Enzo E et al. Negative control of Smad activity by ectodermin/Tif1 gamma patterns the mammalian embryo. Development 2010; 137(15):2571–2578.PubMedCrossRefGoogle Scholar
  58. 58.
    Dupont S, Mamidi A, Cordenonsi M et al. FAM/USP9x, a deubiquitinating enzyme essential for TGFbeta signaling, controls Smad4 monoubiquitination. Cell 2009; 136(1): 123–135.PubMedCrossRefGoogle Scholar
  59. 59.
    Agricola E, Randall RA, Gaarenstroom T et al. Recruitment of TIF1 gamma to chromatin via its PHD finger-bromodomain activates its ubiquitin ligase and transcriptional repressor activities. Mol Cell 2011; 43(1):85–96.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Francesca Petrera
    • 1
  • Germana Meroni
    • 1
  1. 1.Cluster in BiomedicineCBM S.c.r.lTriesteItaly

Personalised recommendations