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Molecular Genetics of Drosophila Development

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: 15 May 2024 | Viewed by 12041

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Dr. Nadezhda Vorobyeva

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Institute of Gene Biology, Russian Academy of Sciences, Moscow 119334, Russia
Interests: development of Drosophila melanogaster; ecdysone hormone; tissue-specific transcription regulation; molecular mechanisms of transcription regulation; multiprotein transcriptional complexes

Special Issue Information

Dear Colleagues,

For more than a century, Drosophila has been used by researchers to establish links between individual genes and their functions in developmental physiological processes. Thanks to the efforts of many researchers, the functions of many genes have been linked to each other, leading to the description of the gene cascades that control development: Hippo, Notch, Hedgehog, Wnt/Wingless, ecdysone cascade, etc.

At present, the vast amount of data generated by high-throughput methods challenges our approaches to describing the gene networks that drive development. An excess of information complicates the search for and selection of significant relationships between genes.

At the same time, we now have the experimental power to test ideas regarding the mechanisms that control Drosophila development, which were put forward years ago but have not been tested in detail. For instance, in the near future, we should expect a description of mechanisms leading to the activation of the final tissue-specific target genes of the ecdysone hormone, which are carried out with the participation of the ecdysone receptor and regulators–components of the ecdysone cascade. Previously, the study of such a large number of activated genes in a single experiment was difficult to imagine. The search for and description of not just gene cascades but genetic networks and programs driving the Drosophila development seems to be a matter for the near future.

Modern technical approaches make it possible to test the novel hypotheses on the work of Drosophila developmental genes at a deeper level than ever before. It's important to remember that already established views on the mechanisms of developmental genes regulation should also be experimentally verified at a new technical level.

The aim of this Special Issue is to collect manuscripts describing both old and new genetic circuits, as well as individual genes that drive the Drosophila development.

Dr. Nadezhda Vorobyeva
Guest Editor

Manuscript Submission Information

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Keywords

Drosophila development
metamorphosis
imaginal discs
differentiation
tissue specification
regeneration
proliferation
neural stem cells
nuclear receptor
ecdysone cascade
hippo signalling pathway
notch signalling pathway
hedgehog signalling pathway
wnt/wingless signalling pathway

Published Papers (12 papers)

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18 pages, 6867 KiB

Open AccessArticle

Development of a New Model System to Study Long-Distance Interactions Supported by Architectural Proteins

by Larisa Melnikova, Varvara Molodina, Pavel Georgiev and Anton Golovnin

Int. J. Mol. Sci. 2024, 25(9), 4617; https://doi.org/10.3390/ijms25094617 - 23 Apr 2024

Viewed by 326

Abstract

Chromatin architecture is critical for the temporal and tissue-specific activation of genes that determine eukaryotic development. The functional interaction between enhancers and promoters is controlled by insulators and tethering elements that support specific long-distance interactions. However, the mechanisms of the formation and maintenance of long-range interactions between genome regulatory elements remain poorly understood, primarily due to the lack of convenient model systems. Drosophila became the first model organism in which architectural proteins that determine the activity of insulators were described. In Drosophila, one of the best-studied DNA-binding architectural proteins, Su(Hw), forms a complex with Mod(mdg4)-67.2 and CP190 proteins. Using a combination of CRISPR/Cas9 genome editing and attP-dependent integration technologies, we created a model system in which the promoters and enhancers of two reporter genes are separated by 28 kb. In this case, enhancers effectively stimulate reporter gene promoters in cis and trans only in the presence of artificial Su(Hw) binding sites (SBS), in both constructs. The expression of the mutant Su(Hw) protein, which cannot interact with CP190, and the mutation inactivating Mod(mdg4)-67.2, lead to the complete loss or significant weakening of enhancer–promoter interactions, respectively. The results indicate that the new model system effectively identifies the role of individual subunits of architectural protein complexes in forming and maintaining specific long-distance interactions in the D. melanogaster model. Full article

(This article belongs to the Special Issue Molecular Genetics of Drosophila Development)

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13 pages, 14562 KiB

Open AccessArticle

Dynamic Cytoophidia during Late-Stage Drosophila Oogenesis

by Shi-Qi Zhang and Ji-Long Liu

Int. J. Mol. Sci. 2024, 25(5), 2575; https://doi.org/10.3390/ijms25052575 - 23 Feb 2024

Cited by 1 | Viewed by 1391

Abstract

CTP synthase (CTPS) catalyzes the final step of de novo synthesis of CTP. CTPS was first discovered to form filamentous structures termed cytoophidia in Drosophila ovarian cells. Subsequent studies have shown that cytoophidia are widely present in cells of three life domains. In the Drosophila ovary model, our previous studies mainly focused on the early and middle stages, with less involvement in the later stages. In this work, we focus on the later stages of female germline cells in Drosophila. We use live-cell imaging to capture the continuous dynamics of cytoophidia in Stages 10–12. We notice the heterogeneity of cytoophidia in the two types of germline cells (nurse cells and oocytes), manifested in significant differences in morphology, distribution, and dynamics. Surprisingly, we also find that neighboring nurse cells in the same egg chamber exhibit multiple dynamic patterns of cytoophidia over time. Although the described dynamics may be influenced by the in vitro incubation conditions, our observation provides an initial understanding of the dynamics of cytoophidia during late-stage Drosophila oogenesis. Full article

(This article belongs to the Special Issue Molecular Genetics of Drosophila Development)

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13 pages, 25330 KiB

Open AccessArticle

Connecting Hippo Pathway and Cytoophidia in Drosophila Posterior Follicle Cells

by Rui-Yu Weng, Lei Zhang and Ji-Long Liu

Int. J. Mol. Sci. 2024, 25(3), 1453; https://doi.org/10.3390/ijms25031453 - 25 Jan 2024

Cited by 1 | Viewed by 646

Abstract

CTP synthase (CTPS), the rate-limiting enzyme in the de novo synthesis of CTP, assembles into a filamentous structure termed the cytoophidium. The Hippo pathway regulates cell proliferation and apoptosis. The relationship of the nucleotide metabolism with the Hippo pathway is little known. Here, we study the impact of the Hippo pathway on the cytoophidium in Drosophila melanogaster posterior follicle cells (PFCs). We find that the inactivation of the Hippo pathway correlates with reduced cytoophidium length and number within PFCs. During the overexpression of CTPS, the presence of Hippo mutations also reduces the length of cytoophidia in PFCs. In addition, we observe that knocking down CTPS mitigates hpo (Hippo)-associated over-proliferation. In summary, our results suggest that there is a connection between the Hippo pathway and the nucleotide biosynthesis enzyme CTPS in PFCs. Full article

(This article belongs to the Special Issue Molecular Genetics of Drosophila Development)

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16 pages, 3585 KiB

Open AccessArticle

New Functional Motifs for the Targeted Localization of Proteins to the Nucleolus in Drosophila and Human Cells

by Anna A. Ogienko, Mariya O. Korepina, Alexey V. Pindyurin and Evgeniya S. Omelina

Int. J. Mol. Sci. 2024, 25(2), 1230; https://doi.org/10.3390/ijms25021230 - 19 Jan 2024

Viewed by 795

Abstract

The nucleolus is a significant nuclear organelle that is primarily known for its role in ribosome biogenesis. However, emerging evidence suggests that the nucleolus may have additional functions. Particularly, it is involved in the organization of the three-dimensional structure of the genome. The nucleolus acts as a platform for the clustering of repressed chromatin, although this process is not yet fully understood, especially in the context of Drosophila. One way to study the regions of the genome that cluster near the nucleolus in Drosophila demands the identification of a reliable nucleolus-localizing signal (NoLS) motif(s) that can highly specifically recruit the protein of interest to the nucleolus. Here, we tested a series of various NoLS motifs from proteins of different species, as well as some of their combinations, for the ability to drive the nucleolar localization of the chimeric H2B-GFP protein. Several short motifs were found to effectively localize the H2B-GFP protein to the nucleolus in over 40% of transfected Drosophila S2 cells. Furthermore, it was demonstrated that NoLS motifs derived from Drosophila proteins exhibited greater efficiency compared to that of those from other species. Full article

(This article belongs to the Special Issue Molecular Genetics of Drosophila Development)

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17 pages, 5644 KiB

Open AccessArticle

The N-Terminal Part of Drosophila CP190 Is a Platform for Interaction with Multiple Architectural Proteins

by Anton Golovnin, Larisa Melnikova, Valentin Babosha, Galina V. Pokholkova, Ivan Slovohotov, Anastasia Umnova, Oksana Maksimenko, Igor F. Zhimulev and Pavel Georgiev

Int. J. Mol. Sci. 2023, 24(21), 15917; https://doi.org/10.3390/ijms242115917 - 02 Nov 2023

Cited by 1 | Viewed by 777

Abstract

CP190 is a co-factor in many Drosophila architectural proteins, being involved in the formation of active promoters and insulators. CP190 contains the N-terminal BTB/POZ (Broad-Complex, Tramtrack and Bric a brac/POxvirus and Zinc finger) domain and adjacent conserved regions involved in protein interactions. Here, we examined the functional roles of these domains of CP190 in vivo. The best-characterized architectural proteins with insulator functions, Pita, Su(Hw), and dCTCF, interacted predominantly with the BTB domain of CP190. Due to the difficulty of mutating the BTB domain, we obtained a transgenic line expressing a chimeric CP190 with the BTB domain of the human protein Kaiso. Another group of architectural proteins, M1BP, Opbp, and ZIPIC, interacted with one or both of the highly conserved regions in the N-terminal part of CP190. Transgenic lines of D. melanogaster expressing CP190 mutants with a deletion of each of these domains were obtained. The results showed that these mutant proteins only partially compensated for the functions of CP190, weakly binding to selective chromatin sites. Further analysis confirmed the essential role of these domains in recruitment to regulatory regions associated with architectural proteins. We also found that the N-terminal of CP190 was sufficient for recruiting Z4 and Chromator proteins and successfully achieving chromatin opening. Taken together, our results and the results of previous studies showed that the N-terminal region of CP190 is a platform for simultaneous interaction with various DNA-binding architectural proteins and transcription complexes. Full article

(This article belongs to the Special Issue Molecular Genetics of Drosophila Development)

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19 pages, 8161 KiB

Open AccessArticle

The MADF-BESS Protein CP60 Is Recruited to Insulators via CP190 and Has Redundant Functions in Drosophila

by Larisa Melnikova, Varvara Molodina, Valentin Babosha, Margarita Kostyuchenko, Pavel Georgiev and Anton Golovnin

Int. J. Mol. Sci. 2023, 24(19), 15029; https://doi.org/10.3390/ijms241915029 - 09 Oct 2023

Cited by 2 | Viewed by 895

Abstract

Drosophila CP190 and CP60 are transcription factors that are associated with centrosomes during mitosis. CP190 is an essential transcription factor and preferentially binds to housekeeping gene promoters and insulators through interactions with architectural proteins, including Su(Hw) and dCTCF. CP60 belongs to a family of transcription factors that contain the N-terminal MADF domain and the C-terminal BESS domain, which is characterized by the ability to homodimerize. In this study, we show that the conserved CP60 region adjacent to MADF is responsible for interacting with CP190. In contrast to the well-characterized MADF-BESS transcriptional activator Adf-1, CP60 is recruited to most chromatin sites through its interaction with CP190, and the MADF domain is likely involved in protein–protein interactions but not in DNA binding. The deletion of the Map60 gene showed that CP60 is not an essential protein, despite the strong and ubiquitous expression of CP60 at all stages of Drosophila development. Although CP60 is a stable component of the Su(Hw) insulator complex, the inactivation of CP60 does not affect the enhancer-blocking activity of the Su(Hw)-dependent gypsy insulator. Overall, our results indicate that CP60 has an important but redundant function in transcriptional regulation as a partner of the CP190 protein. Full article

(This article belongs to the Special Issue Molecular Genetics of Drosophila Development)

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19 pages, 9307 KiB

Open AccessArticle

Droj2 Facilitates Somatosensory Neurite Sculpting via GTP-Binding Protein Arf102F in Drosophila

by Menglong Rui, Weiyu Kong, Wanting Wang, Ting Zheng, Su Wang and Wei Xie

Int. J. Mol. Sci. 2023, 24(17), 13213; https://doi.org/10.3390/ijms241713213 - 25 Aug 2023

Viewed by 1129

Abstract

Developmental remodeling of neurite is crucial for the accurate wiring of neural circuits in the developing nervous system in both vertebrates and invertebrates, and may also contribute to the pathogenesis of neuropsychiatric disorders, for instance, autism, Alzheimer’s disease (AD), and schizophrenia. However, the molecular underpinnings underlying developmental remodeling are still not fully understood. Here, we have identified DnaJ-like-2 (Droj2), orthologous to human DNAJA1 and DNAJA4 that is predicted to be involved in protein refolding, as a developmental signal promoting dendrite sculpting of the class IV dendritic arborization (C4da) sensory neuron in Drosophila. We further show that Arf102F, a GTP-binding protein previously implicated in protein trafficking, serves downstream of Droj2 to govern neurite pruning of C4da sensory neurons. Intriguingly, our data consistently demonstrate that both Droj2 and Arf102F promote the downregulation of the conserved L1-type cell-adhesion molecule Neuroglian anterior to dendrite pruning. Mechanistically, Droj2 genetically interacts with Arf102F and promotes Neuroglian downregulation to initiate dendrite severing. Taken together, this systematic study sheds light on an unprecedented function of Droj2 and Arf102F in neuronal development. Full article

(This article belongs to the Special Issue Molecular Genetics of Drosophila Development)

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14 pages, 15566 KiB

Open AccessArticle

Cell Cycle Regulation by NF-YC in Drosophila Eye Imaginal Disc: Implications for Synchronization in the Non-Proliferative Region

by Anthony Avellino, Chen-Huan Peng and Ming-Der Lin

Int. J. Mol. Sci. 2023, 24(15), 12203; https://doi.org/10.3390/ijms241512203 - 30 Jul 2023

Viewed by 1247

Abstract

Cell cycle progression during development is meticulously coordinated with differentiation. This is particularly evident in the Drosophila 3rd instar eye imaginal disc, where the cell cycle is synchronized and arrests at the G1 phase in the non-proliferative region (NPR), setting the stage for photoreceptor cell differentiation. Here, we identify the transcription factor Nuclear Factor-YC (NF-YC) as a crucial player in this finely tuned progression, elucidating its specific role in the synchronized movement of the morphogenetic furrow. Depletion of NF-YC leads to extended expression of Cyclin A (CycA) and Cyclin B (CycB) from the FMW to the NPR. Notably, NF-YC knockdown resulted in decreased expression of Eyes absent (Eya) but did not affect Decapentaplegic (Dpp) and Hedgehog (Hh). Our findings highlight the role of NF-YC in restricting the expression of CycA and CycB in the NPR, thereby facilitating cell-cycle synchronization. Moreover, we identify the transcriptional cofactor Eya as a downstream target of NF-YC, revealing a new regulatory pathway in Drosophila eye development. This study expands our understanding of NF-YC’s role from cell cycle control to encompass developmental processes. Full article

(This article belongs to the Special Issue Molecular Genetics of Drosophila Development)

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17 pages, 4046 KiB

Open AccessArticle

Coregulators Reside within Drosophila Ecdysone-Inducible Loci before and after Ecdysone Treatment

by Aleksey N. Krasnov, Aleksandra A. Evdokimova, Marina Yu Mazina, Maksim Erokhin, Darya Chetverina and Nadezhda E. Vorobyeva

Int. J. Mol. Sci. 2023, 24(14), 11844; https://doi.org/10.3390/ijms241411844 - 24 Jul 2023

Viewed by 1157

Abstract

Ecdysone signaling in Drosophila remains a popular model for investigating the mechanisms of steroid action in eukaryotes. The ecdysone receptor EcR can effectively bind ecdysone-response elements with or without the presence of a hormone. For years, EcR enhancers were thought to respond to ecdysone via recruiting coactivator complexes, which replace corepressors and stimulate transcription. However, the exact mechanism of transcription activation by ecdysone remains unclear. Here, we present experimental data on 11 various coregulators at ecdysone-responsive loci of Drosophila S2 cells. We describe the regulatory elements where coregulators reside within these loci and assess changes in their binding levels following 20-hydroxyecdysone treatment. In the current study, we detected the presence of some coregulators at the TSSs (active and inactive) and boundaries marked with CP190 rather than enhancers of the ecdysone-responsive loci where EcR binds. We observed minor changes in the coregulators’ binding level. Most were present at inducible loci before and after 20-hydroxyecdysone treatment. Our findings suggest that: (1) coregulators can activate a particular TSS operating from some distal region (which could be an enhancer, boundary regulatory region, or inactive TSS); (2) coregulators are not recruited after 20-hydroxyecdysone treatment to the responsive loci; rather, their functional activity changes (shown as an increase in H3K27 acetylation marks generated by CBP/p300/Nejire acetyltransferase). Taken together, our findings imply that the 20-hydroxyecdysone signal enhances the functional activity of coregulators rather than promoting their binding to regulatory regions during the ecdysone response. Full article

(This article belongs to the Special Issue Molecular Genetics of Drosophila Development)

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14 pages, 9011 KiB

Open AccessArticle

Drosophila Phosphatase of Regenerating Liver Is Critical for Photoreceptor Cell Polarity and Survival during Retinal Development

by Shu-Fen Chen, Hsin-Lun Hsien, Ting-Fang Wang and Ming-Der Lin

Int. J. Mol. Sci. 2023, 24(14), 11501; https://doi.org/10.3390/ijms241411501 - 15 Jul 2023

Viewed by 1039

Abstract

Establishing apicobasal polarity, involving intricate interactions among polarity regulators, is key for epithelial cell function. Though phosphatase of regenerating liver (PRL) proteins are implicated in diverse biological processes, including cancer, their developmental role remains unclear. In this study, we explore the role of Drosophila PRL (dPRL) in photoreceptor cell development. We reveal that dPRL, requiring a C-terminal prenylation motif, is highly enriched in the apical membrane of developing photoreceptor cells. Moreover, dPRL knockdown during retinal development results in adult Drosophila retinal degeneration, caused by hid-induced apoptosis. dPRL depletion also mislocalizes cell adhesion and polarity proteins like Armadillo, Crumbs, and DaPKC and relocates the basolateral protein, alpha subunit of Na⁺/K⁺-ATPase, to the presumed apical membrane. Importantly, this polarity disruption is not secondary to apoptosis, as suppressing hid expression does not rescue the polarity defect in dPRL-depleted photoreceptor cells. These findings underscore dPRL’s crucial role in photoreceptor cell polarity and emphasize PRL’s importance in establishing epithelial polarity and maintaining cell survival during retinal development, offering new insights into PRL’s role in normal epithelium. Full article

(This article belongs to the Special Issue Molecular Genetics of Drosophila Development)

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Review

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0 pages, 5919 KiB

Open AccessReview

Developmental and Housekeeping Genes: Two Types of Genetic Organization in the Drosophila Genome

by Igor Zhimulev, Tatyana Vatolina, Victor Levitsky and Anton Tsukanov

Int. J. Mol. Sci. 2024, 25(7), 4068; https://doi.org/10.3390/ijms25074068 - 06 Apr 2024

Viewed by 555

Abstract

We developed a procedure for locating genes on Drosophila melanogaster polytene chromosomes and described three types of chromosome structures (gray bands, black bands, and interbands), which differed markedly in morphological and genetic properties. This was reached through the use of our original methods of molecular and genetic analysis, electron microscopy, and bioinformatics data processing. Analysis of the genome-wide distribution of these properties led us to a bioinformatics model of the Drosophila genome organization, in which the genome was divided into two groups of genes. One was constituted by 6562 genes that are expressed in most cell types during life cycle and perform basic cellular functions (the so-called "housekeeping genes"). The other one was made up of 3162 genes that are expressed only at particular stages of development (“developmental genes”). These two groups of genes are so different that we may state that the genome has two types of genetic organization. Different are the timings of their expression, chromatin packaging levels, the composition of activating and deactivating proteins, the sizes of these genes, the lengths of their introns, the organization of the promoter regions of the genes, the locations of origin recognition complexes (ORCs), and DNA replication timings. Full article

(This article belongs to the Special Issue Molecular Genetics of Drosophila Development)

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19 pages, 3303 KiB

Open AccessReview

Polycomb Recruiters Inside and Outside of the Repressed Domains

by Maksim Erokhin, Vladic Mogila, Dmitry Lomaev and Darya Chetverina

Int. J. Mol. Sci. 2023, 24(14), 11394; https://doi.org/10.3390/ijms241411394 - 13 Jul 2023

Viewed by 1307

Abstract

The establishment and stable inheritance of individual patterns of gene expression in different cell types are required for the development of multicellular organisms. The important epigenetic regulators are the Polycomb group (PcG) and Trithorax group (TrxG) proteins, which control the silenced and active states of genes, respectively. In Drosophila, the PcG/TrxG group proteins are recruited to the DNA regulatory sequences termed the Polycomb response elements (PREs). The PREs are composed of the binding sites for different DNA-binding proteins, the so-called PcG recruiters. Currently, the role of the PcG recruiters in the targeting of the PcG proteins to PREs is well documented. However, there are examples where the PcG recruiters are also implicated in the active transcription and in the TrxG function. In addition, there is increasing evidence that the genome-wide PcG recruiters interact with the chromatin outside of the PREs and overlap with the proteins of differing regulatory classes. Recent studies of the interactomes of the PcG recruiters significantly expanded our understanding that they have numerous interactors besides the PcG proteins and that their functions extend beyond the regulation of the PRE repressive activity. Here, we summarize current data about the functions of the PcG recruiters. Full article

(This article belongs to the Special Issue Molecular Genetics of Drosophila Development)

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