Effects of Mutation

Mi-2 was identified in a genome-wide analyses for transcription factors required for proper morphogenesis of Drosophila sensory neuron dendrites

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).

Chromosome condensation during condensin I subunits or topoisomerase II in oocytes only mildly affected chromosome condensation. In contrast, severe undercondensation of chromosomes after depletion of the Mi-2 containing NuRD nucleosome remodelling complex or the protein kinase NHK-1/ballchen. The further phenotypic analysis suggests that Mi-2 and NHK-1 are involved in different pathways in chromosome condensation. The main role of NHK-1 in chromosome condensation is to phosphorylate BAF and suppress its activity in linking chromosomes to nuclear envelope proteins. Further this study showed that NHK-1 is important for chromosome condensation in mitosis as well as in oocytes (Nikalayevich, 2014).

During cell division, chromosomes undergo morphological changes from a cloud-like interphase morphology into rod-like structures. This transformation is referred to as chromosome condensation. Chromosome condensation is important for faithful chromosome segregation during cell division. The organisation of condensed metaphase chromosomes has been a focus of debate for a long time, and various models have been proposed. One model is that there is a hierarchical organisation, starting from nucleosomes folded into a 30-nm fibre, which form larger and larger loops. Another long-standing, and not mutually exclusive, model is that there is a chromosome scaffold, which has been observed after removal of DNA and most of the chromosome proteins from the metaphase chromosomes. However, the existence and the biological role of this scaffold are subjects of continuous discussion. The most recently proposed model is a polymer model based on data from a chromosome conformation capture method. This proposes that there is a compressed linear array of loops without hierarchical organisation (Nikalayevich, 2014).

Among thousands of proteins found in metaphase chromosomes, condensin complexes and topoisomerase II have been studied most extensively for their involvement in chromosome condensation during cell division. The condensin complex was originally found as the main chromosome condensation factor in Xenopus extract. The involvement of condensin complexes in this process has been demonstrated in many systems. Higher eukaryotes have two condensin complexes, condensin I and II. The two complexes appear to have different localisations and functions. The exact molecular mechanism by which condensin functions has not been established, but it has an ability to positively supercoil DNA (Nikalayevich, 2014).

It has been demonstrated in several systems that topoisomerase II is required for chromosome structure as well as correct chromosome segregation in mitosis and meiosis. Topoisomerase II is present on chromosomes in mitosis and meiosis and is also enriched on centromeres and pericentromeric regions during meiosis. Topoisomerase II decatenates supercoiled DNA by introducing temporary double-strand DNA breaks, and it has been suggested and demonstrated that topoisomerase II acts in opposition to condensin and KIF4A. Both condensin and topoisomerase II are required for the correct chromatin structure of the centromere (Nikalayevich, 2014).

Despite extensive research on the roles of condensin and topoisomerase II in chromosome condensation, some evidence casts doubts on whether these proteins are the only major factors involved in chromosome condensation. In some systems, chromosomes are still able to condense, with various abnormalities, after depletion of condensin subunits. Depletion of condensin does not prevent condensation of chromosomes until the initiation of anaphase, but causes chromosomes to decondense prematurely during anaphase. This has led to a proposal that there is a 'regulator of chromosome architecture' (RCA), an as yet unidentified factor, which acts redundantly with condensin to condense metaphase chromosomes (Nikalayevich, 2014).

Evidence suggests that there are crucial chromosome condensation factors other than condensin and topoisomerase II. Recently, attempts have been made to find new chromosome condensation factors. For example, a chromosome condensation assay allowed high-throughput analysis of genes required for chromosome condensation in fission yeast. In that study, eight new conditional condensin alleles were discovered, together with a new role for DNA polymerase ε (pol ε) and F-box DNA helicase I in chromosome condensation. In addition, a very recent study has identified mutations in several genes that cause chromosome segregation defects similar to those induced by depletion of condensin. Four out of five of these genes encode components of the nucleosome-remodelling complexes (Nikalayevich, 2014)

This report describes the first use of Drosophila oocytes to study chromosome condensation. RNA interference (RNAi)-mediated depletion of a set of chromosomal proteins revealed that depletion of the nucleosome-remodelling protein Mi-2 and the protein kinase NHK-1 (Nucleosomal histone kinase-1, also known as Ballchen in Drosophila) resulted in much more severe defects than depletion of well-known chromosome condensation factors. The condensation defects of Mi-2 and NHK-1 depletion were distinct from each other, suggesting that these proteins function in different pathways. This study found that the main NHK-1 action in chromosome condensation is to suppress Barrier-to-autointergration factor (BAF) activity, which functions to link nuclear envelope proteins to chromosomes (Nikalayevich, 2014)

Therefore, knockdown of potential chromosomal proteins or regulators by RNAi in oocytes has identified new factors promoting chromosome condensation (the NuRD complex and NHK-1) as well as known factors (condensin I, topoisomerase II and Aurora B). Depletion of the protein kinase NHK-1 and the NuRD nucleosome remodelling complex containing Mi-2 caused severe chromosome condensation defects that were distinct from each other. Further study revealed that BAF is the main substrate of NHK-1 for its chromosome condensation function and that NHK-1 promotes chromosome condensation by suppressing the linker activity of BAF between nuclear envelope proteins and DNA. Finally, it was shown that NHK-1 is also important for chromosome condensation in mitosis (Nikalayevich, 2014)

The Drosophila oocyte combined with RNAi is an excellent system for research of chromosome condensation, which complements commonly used mitotic systems. Firstly, Drosophila oocytes grow enormously in volume between completion of pre-meiotic mitosis and recombination and chromosome condensation. Small hairpin RNA (shRNA) expression can be induced after the protein executes its role in the previous mitosis and/or recombination but prior to oocyte growth. Even if the target protein is stable, it becomes sufficiently diluted before chromosome condensation in oocytes. This is in contrast to mitotic cycles where cells only double in size between divisions. Secondly, Drosophila oocytes arrest in metaphase of the first meiotic division. This allows chromosome defects to be studied in the first division after the target protein is depleted, rather than as a mixture of defects accumulated through multiple divisions caused by a gradual decrease of the protein. Finally, as oocytes are large, the condensation state of chromosomes can be clearly observed without mechanical treatment such as squashing or spreading. Therefore, RNAi in Drosophila oocytes could be a powerful system to study chromosome condensation, although negative results should be interpreted with caution as they might be caused by insufficient depletion, genetic redundancy or cell-type-specific function (Nikalayevich, 2014)

Indeed, in this study, a small-scale survey of chromosomal proteins, new chromosome condensation factors were identified in addition to well-known ones, demonstrating the effectiveness of Drosophila oocytes as a research system. Well-known factors, including condensin I subunits, topoisomerase II and Aurora B, showed milder chromosome condensation defects. Knockdown of topoisomerase II or condensin I showed similar condensation defects, and appeared to affect mainly centromeric and/or pericentromeric regions. The previous reports in mitosis are consistent with these result, suggesting that these two factors are not the main condensation factors in mitosis or in meiosis (Nikalayevich, 2014)

A previous study of Mi-2 in Drosophila suggested that it promotes decondensation of chromosomes because overexpression of wild-type Mi-2 results in chromosome decondensation in polytene or mitotic cells and overexpression of dominant-negative Mi-2 results in overcondensation. In the current study, Mi-2 RNAi in oocytes showed chromosome decondensation, whereas in a preliminary study in neuroblasts Mi-2 RNAi did not show chromosome decondensation. The difference from the previous study might be due to the method of disrupting the Mi-2 function or cell types used for the studies. It is argued that the phenotype caused by RNAi in oocytes is a better reflection of the in vivo function. RNAi of other NuRD subunits indicated that the NuRD complex is important for chromosome condensation (Nikalayevich, 2014)

How does the NuRD complex promote chromosome condensation? It is possible that nucleosome remodelling is directly required during chromosome condensation. For example, proper positioning of nucleosomes might be important for full chromosome condensation. Indeed, other nucleosome remodelling complexes have been suggested to be involved in chromosome condensation in fission yeast. Alternatively, histone deacetylase acivity of the NuRD complex might be important for chromosome condensation, as histone modifications are a major way to regulate chromosome structure. The possibility that NuRD acts through transcription of other chromosome condensation factors cannot be excluded, as it is known to regulate gene transcription. Further studies using more sophisticated mutations would help to distinguish these possibilities (Nikalayevich, 2014)

Knockdown of NHK-1 resulted in severe chromosome condensation defects in nearly all oocytes. Previously, involvement of NHK-1 or its orthologues in metaphase chromosome condensation has not been reported, although overexpression of the human orthologue disrupts chromatin organisation in interphase. None of the three female sterile nhk-1 mutants showed chromosome condensation defects in metaphase I in oocytes. This might be because the minimal NHK-1 activity required for producing viable adults is sufficient to allow chromosome condensation in oocytes. Female-germline-specific RNAi is likely to have achieved greater depletion of NHK-1 in oocytes. This study showed that phosphorylation of BAF, thus inactivating its linking of DNA to LEM-domain-containing inner nuclear membrane proteins, is the major role of NHK-1 in chromosome condensation in oocytes. However, NHK-1 might regulate multiple pathways during condensation, for example, it has been shown that it is required for histone 2A phosphorylation and condensin recruitment in prophase I oocytes (Nikalayevich, 2014)

A crucial question is whether the chromosome condensation defect is a direct consequence of NHK-1 loss or a secondary consequence of a karyosome defect in prophase I oocytes. Evidence indicates that the compact karyosome in the prophase I nucleus and chromosome condensation in metaphase I are at least partly independent. In female-sterile hypomophic nhk-1 mutants, chromatin organisation in prophase I oocytes is defective, but metaphase I chromosomes are properly condensed in mature oocytes. By contrast, in Mi-2 RNAi oocytes, the karyosome is normal in prophase I, but chromosomes become undercondensed after nuclear envelope breakdown in some metaphase I oocytes. Furthermore, as chromosome condensation in mitosis is also defective in nhk-1 mutants, the role for NHK-1 in chromosome condensation must be at least partly independent from meiosis-specific chromatin organisation. Therefore, release of LEM-containing nuclear envelope proteins from chromosomes might be a prerequisite for proper chromosome condensation (Nikalayevich, 2014)

In conclusion, this targeted survey using RNAi in Drosophila oocytes has already identified new factors required for chromosome condensation. Further analysis provided new insights into the molecular mechanism of condensation including the release of nuclear envelope proteins from chromosomes and nucleosome remodelling and/or histone deacetylation as essential steps for condensation. In future, a larger scale screen of putative chromosomal proteins might prove to be fruitful (Nikalayevich, 2014)


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Mi-2: Biological Overview | Evolutionary Homologs | Developmental Biology | Regulation

date revised: 10 April 2015

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