Regulation of mRNA translation is especially important during cellular and developmental processes. Many evolutionarily conserved proteins act in the context of multiprotein complexes and modulate protein translation both at the spatial and the temporal levels. Among these, Bicaudal C constitutes a family of RNA binding proteins whose founding member was first identified in Drosophila and contains orthologs in vertebrates. We discuss recent advances towards understanding the functions of these proteins in the context of the cellular and developmental biology of many model organisms and their connection to human disease. 1. Introduction Translational regulation of mRNA distributed asymmetrically in the early Drosophila embryo underlies pattern formation and germ cell specification. Furthermore, expression of certain proteins occurs only at definite stages of development. Exquisite, often partially redundant mechanisms of control ensure the coordination of the spatial and temporal expression of proteins with morphogenetic potential. These mechanisms have been reviewed recently [6]. Here we will discuss the case of one of such translational regulators, Bicaudal C (Bic-C), which is evolutionarily conserved, and for which there is recent accumulating functional evidence from both invertebrate and vertebrate model organisms suggesting that Bic-C is a fundamental regulator of cellular processes and an outstanding example of the fascinating complexity of the developmental mechanisms. 2. Materials and Methods The sequences shown in this paper are listed in Table 1, and they were recovered by running BLAST [7] with the Drosophila sequence and the NCBI sequence database, using the Homologene feature at the NCBI. The sequences for the different Drosophila species were retrieved from FlyBase [8]. Sequences were aligned with Clustal W [1, 2]. Table 1: Sequences used in this study. 3. Results and Discussion 3.1. Bic-C The Bic-C gene was originally identified during a Drosophila screen for maternal genes affecting embryonic polarity [9]. In fact, adult females bearing Bic-C mutations in one of their second chromosomes produce embryos exhibiting anterior-posterior defects of severity ranging from anterior defects, to the development of bicaudal embryos composed of as few as four segments arranged as two, mirror-image posterior ends, to embryos that fail to cellularize [3]. This pleiotropy indicates that Bic-C participates in (or influences) many different pathways. Early work demonstrated that Bic-C is required during oogenesis to establish anterior-posterior polarity
References
[1]
M. A. Larkin, G. Blackshields, N. P. Brown et al., “Clustal W and Clustal X version 2.0,” Bioinformatics, vol. 23, no. 21, pp. 2947–2948, 2007.
[2]
M. Goujon, H. McWilliam, W. Li et al., “A new bioinformatics analysis tools framework at EMBL-EBI,” Nucleic Acids Research, vol. 38, pp. W695–W699, 2010.
[3]
M. Mahone, E. E. Saffman, and P. F. Lasko, “Localized Bicaudal-C RNA encodes a protein containing a KH domain, the RNA binding motif of FMR1,” The Embo Journal, vol. 14, no. 9, pp. 2043–2055, 1995.
[4]
R. D. Finn, J. Mistry, J. Tate et al., “The Pfam protein families database,” Nucleic Acids Research, vol. 38, supplement 1, pp. D211–D222, 2010.
[5]
M. Ashburner, P. Thompson, J. Roote et al., “The genetics of a small autosomal region of Drosophila melanogaster containing the structural gene for alcohol dehydrogenase—VII. Characterization of the region around the snail and cactus loci,” Genetics, vol. 126, no. 3, pp. 679–694, 1990.
[6]
P. Lasko, “Posttranscriptional regulation in Drosophila oocytes and early embryos,” Wiley Interdisciplinary Reviews: RNA, vol. 2, no. 3, pp. 408–416, 2011.
[7]
S. F. Altschul, T. L. Madden, A. A. Sch？ffer et al., “Gapped BLAST and PSI-BLAST: a new generation of protein database search programs,” Nucleic Acids Research, vol. 25, no. 17, pp. 3389–3402, 1997.
[8]
P. McQuilton, S. E. St Pierre, and J. Thurmond, “FlyBase 101—the basics of navigating flyBase,” Nucleic Acids Research, vol. 40, no. 1, pp. D706–D714, 2012.
[9]
J. Mohler and E. F. Wieschaus, “Dominant maternal-effect mutations of Drosophila melanogaster causing the production of double-abdomen embryos,” Genetics, vol. 112, no. 4, pp. 803–822, 1986.
[10]
T. Schupbach and E. Wieschaus, “Germline autonomy of maternal-effect mutations altering the embryonic body pattern of Drosophila,” Developmental Biology, vol. 113, no. 2, pp. 443–448, 1986.
[11]
N. V. Grishin, “KH domain: one motif, two folds,” Nucleic Acids Research, vol. 29, no. 3, pp. 638–643, 2001.
[12]
K. Nakel, S. A. Hartung, F. Bonneau, C. R. Eckmann, and E. Conti, “Four KH domains of the C. elegans Bicaudal-C ortholog GLD-3 form a globular structural platform,” RNA, vol. 16, no. 11, pp. 2058–2067, 2010.
[13]
C. A. Kim and J. U. Bowie, “SAM domains: uniform structure, diversity of function,” Trends in Biochemical Sciences, vol. 28, no. 12, pp. 625–628, 2003.
[14]
E. E. Saffman, S. Styhler, K. Rother, W. Li, S. Richard, and P. Lasko, “Premature translation of oskar in oocytes lacking the RNA-binding protein Bicaudal-C,” Molecular and Cellular Biology, vol. 18, no. 8, pp. 4855–4862, 1998.
[15]
J. Chicoine, P. Benoit, C. Gamberi, M. Paliouras, M. Simonelig, and P. Lasko, “Bicaudal-C Recruits CCR4-NOT deadenylase to target mRNAs and regulates Oogenesis, Cytoskeletal organization, and its own expression,” Developmental Cell, vol. 13, no. 5, pp. 691–704, 2007.
[16]
D. J. Bouvrette, S. J. Price, and E. C. Bryda, “K homology domains of the mouse polycystic kidney disease-related protein, Bicaudal-C (Bicc1), mediate RNA binding in vitro,” Nephron Experimental Nephrology, vol. 108, no. 1, pp. e27–e34, 2008.
[17]
B. M. Lunde, C. Moore, and G. Varani, “RNA-binding proteins: modular design for efficient function,” Nature Reviews, vol. 8, no. 6, pp. 479–490, 2007.
[18]
A. J. Peterson, M. Kyba, D. Bornemann, K. Morgan, H. W. Brock, and J. Simon, “A domain shared by the Polycomb group proteins Scm and ph mediates heterotypic and homotypic interactions,” Molecular and Cellular Biology, vol. 17, no. 11, pp. 6683–6692, 1997.
[19]
F. Qiao and J. U. Bowie, “The many faces of SAM,” Science's STKE, vol. 2005, no. 286, article re7, 2005.
[20]
M. J. Knight, C. Leettola, M. Gingery, H. Li, and J. U. Bowie, “A human sterile alpha motif domain polymerizome,” Protein Science, vol. 20, no. 10, pp. 1697–1706, 2011.
[21]
T. Chen, B. B. Damaj, C. Herrera, P. Lasko, and S. Richard, “Self-association of the single-KH-domain family members Sam68, GRP33, GLD-1, and Qk1: role of the KH domain,” Molecular and Cellular Biology, vol. 17, no. 10, pp. 5707–5718, 1997.
[22]
M. Di Fruscio, T. Chen, S. Bonyadi, P. Lasko, and S. Richard, “The identification of two Drosophila K homology domain proteins: KEP1 and SAM are members of the Sam68 family of GSG domain proteins,” Journal of Biological Chemistry, vol. 273, no. 46, pp. 30122–30130, 1998.
[23]
C. R. Eckmann, S. L. Crittenden, N. Suh, and J. Kimble, “GLD-3 and control of the mitosis/meiosis decision in the germline of Caenorhabditis elegans,” Genetics, vol. 168, no. 1, pp. 147–160, 2004.
[24]
T. Aviv, Z. Lin, S. Lau, L. M. Rendl, F. Sicheri, and C. A. Smibert, “The RNA-binding SAM domain of Smaug defines a new family of post-transcriptional regulators,” Nature Structural Biology, vol. 10, no. 8, pp. 614–621, 2003.
[25]
C. Gamberi, O. Johnstone, and P. Lasko, “Drosophila RNA binding proteins,” International Review of Cytology, vol. 248, pp. 43–139, 2006.
[26]
C. Maisonneuve, I. Guilleret, P. Vick et al., “Bicaudal C, a novel regulator of Dvl signaling abutting RNA-processing bodies, controls cilia orientation and leftward flow,” Development, vol. 136, no. 17, pp. 3019–3030, 2009.
[27]
U. Tran, L. Zakin, A. Schweickert et al., “The RNA-binding protein bicaudal C regulates polycystin 2 in the kidney by antagonizing miR-17 activity,” Development, vol. 137, no. 7, pp. 1107–1116, 2010.
[28]
J. Schultz, C. P. Ponting, K. Hofmann, and P. Bork, “SAM as a protein interaction domain involved in developmental regulation,” Protein Science, vol. 6, no. 1, pp. 249–253, 1997.
[29]
C. R. Eckmann, B. Kraemer, M. Wickens, and J. Kimble, “GLD-3, a bicaudal-C homolog that inhibits FBF to control germline sex determination in C. elegans,” Developmental Cell, vol. 3, no. 5, pp. 697–710, 2002.
[30]
L. Wang, C. R. Eckmann, L. C. Kadyk, M. Wickens, and J. Kimble, “A regulatory cytoplasmic poly(A) polymerase in Caenorhabditis elegans,” Nature, vol. 419, no. 6904, pp. 312–316, 2002.
[31]
J. M. Kugler, J. Chicoine, and P. Lasko, “Bicaudal-C associates with a trailer hitch/Me31B complex and is required for efficient gurken secretion,” Developmental Biology, vol. 328, no. 1, pp. 160–172, 2009.
[32]
M. J. Snee and P. M. Macdonald, “Bicaudal C and trailer hitch have similar roles in gurken mRNA localization and cytoskeletal organization,” Developmental Biology, vol. 328, no. 2, pp. 434–444, 2009.
[33]
M. K. Jaglarz, M. Kloc, W. Jankowska, B. Szymanska, and S. M. Bilinski, “Nuage morphogenesis becomes more complex: two translocation pathways and two forms of nuage coexist in Drosophila germline syncytia,” Cell and Tissue Research, vol. 344, no. 1, pp. 169–181, 2011.
[34]
M. J. Snee and P. M. Macdonald, “Dynamic organization and plasticity of sponge bodies,” Developmental Dynamics, vol. 238, no. 4, pp. 918–930, 2009.
[35]
M. Wilsch-Br？uninger, H. Schwarz, and C. Nüsslein-Volhard, “A sponge-like structure involved in the association and transport of maternal products during Drosophila oogenesis,” Journal of Cell Biology, vol. 139, no. 3, pp. 817–829, 1997.
[36]
M. Olszewska, J. J. Bujarski, and M. Kurpisz, “P-bodies and their functions during mRNA cell cycle: mini-review,” Cell Biochemistry and Function, vol. 30, no. 3, pp. 177–182, 2012.
[37]
R. Parker and U. Sheth, “P bodies and the control of mRNA translation and degradation,” Molecular Cell, vol. 25, no. 5, pp. 635–646, 2007.
[38]
C. Y. Chen and A. B. Shyu, “AU-rich elements: characterization and importance in mRNA degradation,” Trends in Biochemical Sciences, vol. 20, no. 11, pp. 465–470, 1995.
[39]
M. Tucker, R. R. Staples, M. A. Valencia-Sanchez, D. Muhlrad, and R. Parker, “Ccr4p is the catalytic subunit of a Ccr4p/Pop2p/Notp mRNA deadenylase complex in Saccharomyces cerevisiae,” The Embo Journal, vol. 21, no. 6, pp. 1427–1436, 2002.
[40]
M. Tucker, M. A. Valencia-Sanchez, R. R. Staples, J. Chen, C. L. Denis, and R. Parker, “The transcription factor associated Ccr4 and Caf1 proteins are components of the major cytoplasmic mRNA deadenylase in Saccharomyces cerevisiae,” Cell, vol. 104, no. 3, pp. 377–386, 2001.
[41]
J. Chen, Y. C. Chiang, and C. L. Denis, “CCR4, a 3′-5′ poly(A) RNA and ssDNA exonuclease, is the catalytic component of the cytoplasmic deadenylase,” The Embo Journal, vol. 21, no. 6, pp. 1414–1426, 2002.
[42]
S. Thore, F. Mauxion, B. Séraphin, and D. Suck, “X-ray structure and activity of the yeast Pop2 protein: A nuclease subunit of the mRNA deadenylase complex,” EMBO Reports, vol. 4, no. 12, pp. 1150–1155, 2003.
[43]
M. C. Daugeron, F. Mauxion, and B. Séraphin, “The yeast POP2 gene encodes a nuclease involved in mRNA deadenylation,” Nucleic Acids Research, vol. 29, no. 12, pp. 2448–2455, 2001.
[44]
J. Chen, J. Rappsilber, Y. C. Chiang, P. Russell, M. Mann, and C. L. Denis, “Purification and characterization of the 1.0 MDa CCR4-NOT complex identifies two novel components of the complex,” Journal of Molecular Biology, vol. 314, no. 4, pp. 683–694, 2001.
[45]
U. Oberholzer and M. A. Collart, “Characterization of NOT5 that encodes a new component of the Not protein complex,” Gene, vol. 207, no. 1, pp. 61–69, 1998.
[46]
C. J. A. Sigrist, L. Cerutti, E. de Castro et al., “PROSITE, a protein domain database for functional characterization and annotation,” Nucleic Acids Research, vol. 38, pp. D161–D166, 2010.
[47]
C. Temme, S. Zaessinger, S. Meyer, M. Simonelig, and E. Wahle, “A complex containing the CCR4 and CAF1 proteins is involved in mRNA deadenylation in Drosophila,” The Embo Journal, vol. 23, no. 14, pp. 2862–2871, 2004.
[48]
M. R. Kraus, S. Clauin, Y. Pfister, et al., “Two mutations in human BICC1 resulting in Wnt pathway hyperactivity associated with cystic renal dysplasia,” Human Mutation, vol. 33, no. 1, pp. 86–90, 2012.
[49]
T. C. Burn, T. D. Connors, W. R. Dackowski et al., “Analysis of the genomic sequence for the autosomal dominant polycystic kidney disease (PKD1) gene predicts the presence of a leucine-rich repeat: the American PKD1 consortium (APKD1 Consortium),” Human Molecular Genetics, vol. 4, no. 4, pp. 575–582, 1995.
[50]
J. Hughes, C. J. Ward, B. Peral et al., “The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell recognition domains,” Nature Genetics, vol. 10, no. 2, pp. 151–160, 1995.
[51]
T. Mochizuki, G. Wu, T. Hayashi et al., “PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein,” Science, vol. 272, no. 5266, pp. 1339–1342, 1996.
[52]
F. Hildebrandt, E. Otto, C. Rensing et al., “A novel gene encoding an SH3 domain protein is mutated in nephronophthisis type 1,” Nature Genetics, vol. 17, no. 2, pp. 149–153, 1997.
[53]
L. F. Onuchic, L. Furu, Y. Nagasawa et al., “PKHD1, the polycystic kidney and hepatic disease 1 gene, encodes a novel large protein containing multiple immunoglobulin-like plexin-transcription-factor domains and parallel beta-helix 1 repeats,” American Journal of Human Genetics, vol. 70, no. 5, pp. 1305–1317, 2002.
[54]
C. J. Ward, M. C. Hogan, S. Rossetti et al., “The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein,” Nature Genetics, vol. 30, no. 3, pp. 259–269, 2002.
[55]
H. Xiong, Y. Chen, Y. Yi et al., “A novel gene encoding a TIG multiple domain protein is a positional candidate for autosomal recessive polycystic kidney disease,” Genomics, vol. 80, no. 1, pp. 96–104, 2002.
[56]
C. Cogswell, S. J. Price, X. Hou, L. M. Guay-Woodford, L. Flaherty, and E. C. Bryda, “Positional cloning of jcpk/bpk locus of the mouse,” Mammalian Genome, vol. 14, no. 4, pp. 242–249, 2003.
[57]
U. Tran, L. M. Pickney, B. D. ？zpolat, and O. Wessely, “Xenopus bicaudal-C is required for the differentiation of the amphibian pronephros,” Developmental Biology, vol. 307, no. 1, pp. 152–164, 2007.
[58]
D. J. Bouvrette, V. Sittaramane, J. R. Heidel, A. Chandrasekhar, and E. C. Bryda, “Knockdown of bicaudal C in zebrafish (Danio rerio) causes cystic kidneys: a nonmammalian model of polycystic kidney disease,” Comparative Medicine, vol. 60, no. 2, pp. 96–106, 2010.
[59]
Y. Fu, I. Kim, P. Lian et al., “Loss of Bicc1 impairs tubulomorphogenesis of cultured IMCD cells by disrupting E-cadherin-based cell-cell adhesion,” European Journal of Cell Biology, vol. 89, no. 6, pp. 428–436, 2010.
[60]
M. Jovanovic and M. O. Hengartner, “miRNAs and apoptosis: RNAs to die for,” Oncogene, vol. 25, no. 46, pp. 6176–6187, 2006.
[61]
F. S. Neuman-Silberberg and T. Schupbach, “The Drosophila dorsoventral patterning gene gurken produces a dorsally localized RNA and encodes a TGFα-like protein,” Cell, vol. 75, no. 1, pp. 165–174, 1993.
[62]
R. P. Ray and T. Schüpbach, “Intercellular signaling and the polarization of body axes during Drosophila oogenesis,” Genes & Development, vol. 10, no. 14, pp. 1711–1723, 1996.
[63]
J. E. Wilhelm, M. Buszczak, and S. Sayles, “Efficient protein trafficking requires trailer hitch, a component of a ribonucleoprotein complex localized to the ER in Drosophila,” Developmental Cell, vol. 9, no. 5, pp. 675–685, 2005.
