Mi-2
Dendrite arborization patterns are critical determinants of neuronal function. To explore the basis of transcriptional regulation in dendrite pattern formation, RNA interference (RNAi) was used to screen 730 transcriptional regulators and 78 genes involved in patterning the stereotyped dendritic arbors of class I da neurons were identified in Drosophila. Most of these transcriptional regulators affect dendrite morphology without altering the number of class I dendrite arborization (da) neurons and fall primarily into three groups. Group A genes control both primary dendrite extension and lateral branching, hence the overall dendritic field. Nineteen genes within group A act to increase arborization, whereas 20 other genes restrict dendritic coverage. Group B genes appear to balance dendritic outgrowth and branching. Nineteen group B genes function to promote branching rather than outgrowth, and two others have the opposite effects. Finally, 10 group C genes are critical for the routing of the dendritic arbors of individual class I da neurons. Thus, multiple genetic programs operate to calibrate dendritic coverage, to coordinate the elaboration of primary versus secondary branches, and to lay out these dendritic branches in the proper orientation (Parrish, 2006; Full text of article).
To assay for the stereotyped dendrite arborization pattern of class I da neurons (hereafter referred to as class I neurons) in RNAi-based analysis of dendrite development, a Gal4 enhancer trap line (Gal4221) was used that is highly expressed in class I neurons and weakly expressed in class IV neurons during embryogenesis. Because of the simple and stereotyped dendritic arborization patterns of the dorsally located ddaD and ddaE, the studies of dendrite development focused on these two dorsally located class I neurons (Parrish, 2006).
To establish that RNAi is an efficient method to systematically study dendrite development in the Drosophila embryonic PNS, it was demonstrated that injecting embryos with double-stranded RNA (dsRNA) for green fluorescent protein (gfp) is sufficient to attenuate Gal-4221-driven expression of an mCD8::GFP fusion protein as measured by confocal microscopy. Next whether RNAi could efficiently phenocopy loss-of-function mutants known to affect dendrite development was tested. Similar to the mutant phenotype of short stop (shot), which encodes an actin/microtubule cross-linking protein, shot(RNAi) caused routing defects, dorsal overextension, and a reduction in lateral branching of dorsally extended primary dendrites. Likewise, RNAi of sequoia or flamingo resulted in overextension of ddaD and ddaE, RNAi of hamlet resulted in supernumerary class I neurons, and RNAi of tumbleweed resulted in supernumerary class I neurons and a range of arborization defects, consistent with the reported mutant phenotypes. Thus, RNAi is effective in generating reduction of function phenotypes in embryonic class I dendrites (Parrish, 2006).
In contrast to the genes that coordinately affect dorsal dendrite outgrowth and lateral branching/outgrowth, a group of 21 genes (group B) were identified that have opposing effects on dendrite outgrowth and branching, suggesting that dendrite outgrowth and branching might partially antagonize one another. RNAi of 19 of these genes resulted in dorsal overextension of primary dendrites and a reduction in lateral branching/lateral branch extension. In the most severe cases, such as RNAi of the transcriptional repressor snail, dorsal overextension of almost completely unbranched dendrites was found. Like snail(RNAi), RNAi of the nuclear hormone receptor knirps, the transcriptional repressor l(3)mbt, as well as 15 other genes, all caused dorsal overextension of primary dendrites. As in the case of genes that normally limit arborization, RNAi of these genes rarely caused dendrites to cross the dorsal midline (Parrish, 2006).
As an indication of the hypomorphic nature of many of the alleles and maternal rescue of gene function in mutant embryos, focus was place on dendrite defects that were first apparent during larval stages. For example, a mutant allele of Drosophila Mi-2, which encodes a Hunchback-interacting ATP-dependant chromatin remodeling factor, shows only minor defects in late embryonic stages, but shows an obvious reduction in arborization by 72 h after egg laying. Since Mi-2(RNAi) demonstrates that Mi-2 is required for embryonic dendrite arborization, these findings suggest that Mi-2 is continuously required for class I neurons to maintain proper dendrite arborization patterns. Similarly, the dendritic overbranching associated with a P-element insertion allele of Adf1 was first apparent after embryonic stages, although Adf1(RNAi) caused overbranching in embryos. Class I dendritic arbors of Adf1 mutants are indistinguishable from wild-type neurons until 96 h AEL. By 144 h AEL, ddaE arbors of Adf1 mutants showed a greater than twofold increase in branch number when compared with time-matched wild-type controls. Interestingly, ddaD showed only very minor branching defects in Adf1 mutants, suggesting that ddaD and ddaE might have distinct requirements for Adf1. Similarly, mutant alleles of either E(bx) or Elongin C showed dendrite branching defects only at late larval stages. These findings indicate that Adf1, E(bx), and Elongin C are continuously required to inhibit branching in class I neurons, demonstrating that although class I neurons have very little new branching after embryogenesis, they still retain the capacity to branch (Parrish, 2006).
Aubry, F., Mattei, M. G. and Galibert, F. (1998). Identification of a human 17p-located cDNA encoding a protein of the Snf2-like helicase family. Eur. J. Biochem. 254(3): 558-64. PubMed Citation: 9688266
Ballestar, E., Pile, L. A., Wassarman, D. A., Wolffe, A. P. and Wade, P. A. (2001). A Drosophila MBD family member is a transcriptional co-repressor associated with specific genes. Eur. J. Biochem. 268,5397 -540. 11606202
Bouazoune, K., et al. (2002). The dMi-2 chromodomains are DNA binding modules important for ATP-dependent nucleosome mobilization. EMBO J. 21: 2430-2440. 12006495
Brehm, A., et al. (1999). The E7 oncoprotein associates with Mi2 and histone deacetylase activity to promote cell growth. EMBO J. 18(9): 2449-58. PubMed Citation: 10228159
Brehm, A., et al. (2000). dMi-2 and ISWI chromatin remodelling factors have distinct nucleosome binding and mobilization properties. EMBO J. 19(16):4332-41. PubMed Citation: 10944116
Corona, D. F., et al. (1999). ISWI is an ATP-dependent nucleosome remodeling factor. Mol. Cell 3: 239-245. PubMed Citation: 10078206
Fasulo, B., Deuring, R., Murawska, M., Gause, M., Dorighi, K. M., Schaaf, C. A., Dorsett, D., Brehm, A. and Tamkun, J. W. (2012). The Drosophila MI-2 chromatin-remodeling factor regulates higher-order chromatin structure and cohesin dynamics in vivo. PLoS Genet 8: e1002878. Pubmed: 22912596
Feng, Q. and Zhang, Y. (2001). The MeCP1 complex represses transcription through preferential binding, remodeling, and deacetylating methylated nucleosomes. Genes Dev. 15: 827-8324. 11297506
Gong, Z., Brackertz, M. and Renkawitz, R. (2006). SUMO modification enhances p66-mediated transcriptional repression of the Mi-2/NuRD complex. Mol. Cell. Biol. 26(12): 4519-28. 16738318
Guschin, D., et al. (2000). ATP-Dependent histone octamer mobilization and histone deacetylation mediated by the Mi-2 chromatin remodeling complex. Biochemistry 39(18): 5238-45. PubMed Citation: 10819992
Hamiche, A., et al. (1998). ATP-dependent histone octamer sliding mediated by the chromatin remodeling complex NURF. Cell 97(7): 833-42. PubMed Citation: 10399912
Hirose, F., Ohshima, N., Kwon, E.-J., Yoshida, H., Yamaguchi, M. (2002). Drosophila Mi-2 negatively regulates dDREF by inhibiting its DNA-binding activity. Mol. Cell. Biol. 22: 5182-5193. 12077345
Jin, S. G., Jiang, C. L., Rauch, T., Li, H. and Pfeifer, G. P. (2005). MBD3L2 interacts with MBD3 and components of the NuRD complex and can oppose MBD2-MeCP1-mediated methylation silencing. J. Biol. Chem. 280(13): 12700-9. 15701600
Kehle, J., et al. (1998). dMi-2, a Hunchback-interacting protein that functions in Polycomb repression. Science 282(5395): 1897-900. PubMed Citation: 9836641
Kim, J., et al. (1999). Ikaros DNA-binding proteins direct formation of chromatin remodeling complexes in lymphocytes. Immunity 10(3): 345-55. PubMed Citation: 10204490
Kingston, R. E. and Narlikar, G. J. (1999) ATP-dependent remodeling and acetylation as regulators of chromatin fluidity. Genes Dev. 13: 2339-2352. PubMed Citation: 10500090
Koipally, J., et al. (1999). Repression by Ikaros and Aiolos is mediated through histone deacetylase complexes. EMBO J. 18(11): 3090-100. PubMed Citation: 10357820
Kon, C., Cadigan, K. M., da Silva, S. L. and Nusse, R. (2005). Developmental roles of the Mi-2/NURD-associated protein p66 in Drosophila. Genetics 169(4): 2087-100. 15695365
Längst, G., et al. (1999). Nucleosome movement by CHRAC and ISWI without disruption or trans-displacement of the histone octamer. Cell 97: 843-852. PubMed Citation: 10399913
Linder, B., et al. (2007). CHD4/Mi-2β activity is required for the positioning of the mesoderm/neuroectoderm boundary in Xenopus. Genes Dev. 21: 973-983. Medline abstract: 17438000
Marhold, J., Zbylut, M., Lankenau, D. H., Li, M., Gerlich, D., Ballesar, E., Mechler, B. M. and Lyko, F. (2002). Stage-specific chromosomal association of Drosophila dMBD2/3 during genome activation. Chromosoma 111: 13-21. 12068919
Marhold, J., Kramer, K., Kremmer, E. and Lyko, F. (2004). The Drosophila MBD2/3 protein mediates interactions between the MI-2 chromatin complex and CpT/A-methylated DNA. Development 131: 6033-6039. 15537686
Mathieu, E. L., Finkernagel, F., Murawska, M., Scharfe, M., Jarek, M. and Brehm, A. (2012). Recruitment of the ATP-dependent chromatin remodeler dMi-2 to the transcribed region of active heat shock genes. Nucleic Acids Res 40: 4879-4891. Pubmed: 22362736
Murawsky, C. M., et al. (2001). Tramtrack69 interacts with the dMi-2 subunit of the Drosophila NuRD chromatin remodelling complex. EMBO Reports 2: 1089-1094. 11743021
Murawska, M., Hassler, M., Renkawitz-Pohl, R., Ladurner, A. and Brehm, A. (2011). Stress-induced PARP activation mediates recruitment of Drosophila Mi-2 to promote heat shock gene expression. PLoS Genet 7: e1002206. Pubmed: 21829383
O'Neill, D. W., et al. (2000). An ikaros-containing chromatin-remodeling complex in adult-type erythroid cells. Mol. Cell. Biol. 20(20): 7572-82. PubMed Citation: 11003653
Parrish, J. Z., Kim, M. D., Jan, L. Y. and Jan, Y. N. (2006). Genome-wide analyses identify transcription factors required for proper morphogenesis of Drosophila sensory neuron dendrites. Genes Dev. 20(7): 820-35. Medline abstract: 16547170
Polo, S. E., Kaidi, A., Baskcomb, L., Galanty, Y. and Jackson, S. P. (2010). Regulation of DNA-damage responses and cell-cycle progression by the chromatin remodelling factor CHD4. Embo J. 29: 3130-3139. PubMed Citation: 20693977
Scimone, M. L., Meisel, J., Reddien, P. W. (2010). The Mi-2-like Smed-CHD4 gene is required for stem cell differentiation in the planarian Schmidtea mediterranea. Development 137(8): 1231-41. PubMed Citation: 20223763
Solari, F. and Ahringer, J. (2000). NURD-complex genes antagonise Ras-induced vulval development in Caenorhabditis elegans. Curr. Biol. 10(4): 223-6. PubMed Citation: 10704416
Srinivasan, S., et al. (2005). The Drosophila trithorax group protein Kismet facilitates an early step in transcriptional elongation by RNA Polymerase II. Development 132: 1623-1635. 15728673
Tong, J. K., et al. (1998). Chromatin deacetylation by an ATP-dependent nucleosome remodelling complex. Nature 395: 917-921. PubMed Citation: 9804427
Tweedie, S., Ng, H. H., Barlow, A. L., Turner, B. M., Hendrich, B. and Bird, A. (1999). Vestiges of a DNA methylation system in Drosophila melanogaster? Nat. Genet. 23: 389-390. 10581020
Unhavaithaya, Y., et al. (2002). MEP-1 and a homolog of the NURD complex component Mi-2 act together to maintain germline-soma distinctions in C. elegans. Cell 111: 991-1002. 12507426
von Zelewsky, T., et al. (2000). The C. elegans Mi-2 chromatin-remodelling proteins function in vulval cell fate determination. Development 127: 5277-5284. PubMed ID: 11076750
Wade, P. A., et al. (1998). A multiple subunit Mi-2 histone deacetylase from Xenopus laevis cofractionates with an associated Snf2 superfamily ATPase. Curr. Biol. 8(14): 843-6. PubMed ID: 9663395
Wade, P. A., et al. (1999). Mi-2 complex couples DNA methylation to chromatin remodelling and histone deacetylation. Nat. Genet. 23(1): 62-6. PubMed ID: 10471500
Whitehouse, I., et al. (1999). Nucleosome mobilization catalysed by the yeast SWI/SNF complex. Nature 400: 784-787. PubMed ID: 10466730
Woodage, T., et al. (1997). Characterization of the CHD family of proteins. Proc. Natl Acad. Sci. 94: 11472-11477. PubMed ID: 9326634
Xue, Y., et al. (1998). NURD, a novel complex with both ATP-dependent chromatin-remodeling and histone deacetylase activities. Mol. Cell 2 851-861. PubMed ID: 9885572
Yamasaki, Y. and Nishida, Y. (2006). Mi-2 chromatin remodeling factor functions in sensory organ development through proneural gene repression in Drosophila. Dev. Growth Differ. 48(7): 411-8. Medline abstract: 16961588
Zhang, Y., et al. (1998). The dermatomyositis-specific autoantigen Mi2 is a component of a complex containing histone deacetylase and nucleosome remodeling activities. Cell 95(2): 279-89. PubMed ID: 9790534
Zhang, Y., et al. (1999). Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation. Genes Dev. 13(15): 1924-35. PubMed ID: 10444591
date revised: 10 February 2013
Home page: The Interactive Fly © 1997 Thomas B. Brody, Ph.D.
The Interactive Fly resides on the
Society for Developmental Biology's Web server.