Publications by authors named "Wu-Min Deng"

65 Publications

Polyploidy in development and tumor models in Drosophila.

Semin Cancer Biol 2021 Sep 22. Epub 2021 Sep 22.

Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, LA 70112, United States. Electronic address:

Polyploidy, a cell status defined as more than two sets of genomic DNA, is a conserved strategy across species that can increase cell size and biosynthetic production, but the functional aspects of polyploidy are nuanced and vary across cell types. Throughout Drosophila developmental stages (embryo, larva, pupa and adult), polyploid cells are present in numerous organs and help orchestrate development while contributing to normal growth, well-being and homeostasis of the organism. Conversely, increasing evidence has shown that polyploid cells are prevalent in Drosophila tumors and play important roles in tumor growth and invasiveness. Here, we summarize the genes and pathways involved in polyploidy during normal and tumorigenic development, the mechanisms underlying polyploidization, and the functional aspects of polyploidy in development, homeostasis and tumorigenesis in the Drosophila model.
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http://dx.doi.org/10.1016/j.semcancer.2021.09.011DOI Listing
September 2021

Polyploid mitosis and depolyploidization promote chromosomal instability and tumor progression in a Notch-induced tumor model.

Dev Cell 2021 Jul 18;56(13):1976-1988.e4. Epub 2021 Jun 18.

Department of Biochemistry and Molecular Biology, Tulane University Louisiana Center Research Center, New Orleans, LA 70112, USA; Department of Biological Science, Florida State University, Tallahassee, FL 32306, USA. Electronic address:

Ploidy variation is a cancer hallmark and is frequently associated with poor prognosis in high-grade cancers. Using a Drosophila solid-tumor model where oncogenic Notch drives tumorigenesis in a transition-zone microenvironment in the salivary gland imaginal ring, we find that the tumor-initiating cells normally undergo endoreplication to become polyploid. Upregulation of Notch signaling, however, induces these polyploid transition-zone cells to re-enter mitosis and undergo tumorigenesis. Growth and progression of the transition-zone tumor are fueled by a combination of polyploid mitosis, endoreplication, and depolyploidization. Both polyploid mitosis and depolyploidization are error prone, resulting in chromosomal copy-number variation and polyaneuploidy. Comparative RNA-seq and epistasis analysis reveal that the DNA-damage response genes, also active during meiosis, are upregulated in these tumors and are required for the ploidy-reduction division. Together, these findings suggest that polyploidy and associated cell-cycle variants are critical for increased tumor-cell heterogeneity and genome instability during cancer progression.
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http://dx.doi.org/10.1016/j.devcel.2021.05.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282749PMC
July 2021

Developmental regulation of oocyte lipid intake through 'patent' follicular epithelium in .

iScience 2021 Apr 6;24(4):102275. Epub 2021 Mar 6.

Department of Biological Science, Florida State University, Tallahassee, FL 32306-4295, USA.

Epithelia form protective permeability barriers that selectively allow the exchange of material while maintaining tissue integrity under extreme mechanical, chemical, and bacterial loads. Here, we report in the follicular epithelium a developmentally regulated and evolutionarily conserved process "patency", wherein a breach is created in the epithelium at tricellular contacts during mid-vitellogenesis. In , patency exhibits a strict temporal range potentially delimited by the transcription factor Tramtrack69 and a spatial pattern influenced by the dorsal-anterior signals of the follicular epithelium. Crucial for growth and lipid uptake by the oocyte, patency is also exploited by endosymbionts such as . Our findings reveal an evolutionarily conserved and developmentally regulated non-typical epithelial function in a classic model system.
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http://dx.doi.org/10.1016/j.isci.2021.102275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005764PMC
April 2021

A comprehensive in vivo screen for anti-apoptotic miRNAs indicates broad capacities for oncogenic synergy.

Dev Biol 2021 07 1;475:10-20. Epub 2021 Mar 1.

Developmental Biology Program, Sloan Kettering Institute, 1275 York Ave, Box 252, New York, NY, 10065, USA. Electronic address:

microRNAs (miRNAs) are ~21-22 nucleotide (nt) RNAs that mediate broad post-transcriptional regulatory networks. However, genetic analyses have shown that the phenotypic consequences of deleting individual miRNAs are generally far less overt compared to their misexpression. This suggests that miRNA deregulation may have broader phenotypic impacts during disease situations. We explored this concept in the Drosophila eye, by screening for miRNAs whose misexpression could modify the activity of pro-apoptotic factors. Via unbiased and comprehensive in vivo phenotypic assays, we identify an unexpectedly large set of miRNA hits that can suppress the action of pro-apoptotic genes hid and grim. We utilize secondary assays to validate that a subset of these miRNAs can inhibit irradiation-induced cell death. Since cancer cells might seek to evade apoptosis pathways, we modeled this situation by asking whether activation of anti-apoptotic miRNAs could serve as "second hits". Indeed, while clones of the lethal giant larvae (lgl) tumor suppressor are normally eliminated during larval development, we find that diverse anti-apoptotic miRNAs mediate the survival of lgl mutant clones in third instar larvae. Notably, while certain anti-apoptotic miRNAs can target apoptotic factors, most of our screen hits lack obvious targets in the core apoptosis machinery. These data highlight how a genetic approach can reveal distinct and powerful activities of miRNAs in vivo, including unexpected functional synergies during disease or cancer-relevant settings.
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http://dx.doi.org/10.1016/j.ydbio.2021.02.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107139PMC
July 2021

Tumor Allotransplantation in Drosophila melanogaster with a Programmable Auto-Nanoliter Injector.

J Vis Exp 2021 02 2(168). Epub 2021 Feb 2.

Department of Biochemistry and Molecular Biology, Tulane University School of Medicine;

This protocol describes the allotransplantation of tumors in Drosophila melanogaster using an auto-nanoliter injection apparatus. With the use of an autoinjector apparatus, trained operators can achieve more efficient and consistent transplantation results compared to those obtained using a manual injector. Here, we cover topics in a chronological fashion: from the crossing of Drosophila lines, to the induction and dissection of the primary tumor, transplantation of the primary tumor into a new adult host and continued generational transplantation of the tumor for extended studies. As a demonstration, here we use Notch intracellular domain (NICD) overexpression induced salivary gland imaginal ring tumors for generational transplantation. These tumors can first be reliably induced in a transition-zone microenvironment within larval salivary gland imaginal rings, then allografted and cultured in vivo to study continued tumor growth, evolution, and metastasis. This allotransplantation method can be useful in potential drug screening programs, as well as for studying tumor-host interactions.
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http://dx.doi.org/10.3791/62229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316925PMC
February 2021

Deconstructing tumor heterogeneity: the stromal perspective.

Oncotarget 2020 Oct 6;11(40):3621-3632. Epub 2020 Oct 6.

Department of Cell Biology and Physiology, Washington University in St. Louis, St. Louis, MO, USA.

Significant advances have been made towards understanding the role of immune cell-tumor interplay in either suppressing or promoting tumor growth, progression, and recurrence, however, the roles of additional stromal elements, cell types and/or cell states remain ill-defined. The overarching goal of this NCI-sponsored workshop was to highlight and integrate the critical functions of non-immune stromal components in regulating tumor heterogeneity and its impact on tumor initiation, progression, and resistance to therapy. The workshop explored the opposing roles of tumor supportive suppressive stroma and how cellular composition and function may be altered during disease progression. It also highlighted microenvironment-centered mechanisms dictating indolence or aggressiveness of early lesions and how spatial geography impacts stromal attributes and function. The prognostic and therapeutic implications as well as potential vulnerabilities within the heterogeneous tumor microenvironment were also discussed. These broad topics were included in this workshop as an effort to identify current challenges and knowledge gaps in the field.
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http://dx.doi.org/10.18632/oncotarget.27736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546755PMC
October 2020

A single-cell atlas of adult Drosophila ovary identifies transcriptional programs and somatic cell lineage regulating oogenesis.

PLoS Biol 2020 04 27;18(4):e3000538. Epub 2020 Apr 27.

Department of Biological Science, Florida State University, Tallahassee, Florida, United States of America.

Oogenesis is a complex developmental process that involves spatiotemporally regulated coordination between the germline and supporting, somatic cell populations. This process has been modeled extensively using the Drosophila ovary. Although different ovarian cell types have been identified through traditional means, the large-scale expression profiles underlying each cell type remain unknown. Using single-cell RNA sequencing technology, we have built a transcriptomic data set for the adult Drosophila ovary and connected tissues. Using this data set, we identified the transcriptional trajectory of the entire follicle-cell population over the course of their development from stem cells to the oogenesis-to-ovulation transition. We further identify expression patterns during essential developmental events that take place in somatic and germline cell types such as differentiation, cell-cycle switching, migration, symmetry breaking, nurse-cell engulfment, egg-shell formation, and corpus luteum signaling. Extensive experimental validation of unique expression patterns in both ovarian and nearby, nonovarian cells also led to the identification of many new cell type-and stage-specific markers. The inclusion of several nearby tissue types in this data set also led to our identification of functional convergence in expression between distantly related cell types such as the immune-related genes that were similarly expressed in immune cells (hemocytes) and ovarian somatic cells (stretched cells) during their brief phagocytic role in nurse-cell engulfment. Taken together, these findings provide new insight into the temporal regulation of genes in a cell-type specific manner during oogenesis and begin to reveal the relatedness in expression between cell and tissues types.
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http://dx.doi.org/10.1371/journal.pbio.3000538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205450PMC
April 2020

Drosophila Model in Cancer: An Introduction.

Adv Exp Med Biol 2019 ;1167:1-14

Department of Biochemistry and Molecular Biology, Tulane Cancer Center, LCRC, Tulane University School of Medicine, New Orleans, LA, USA.

Cancer is a cumulative manifestation of several complicated disease states that affect multiple organs. Over the last few decades, the fruit fly Drosophila melanogaster, has become a successful model for studying human cancers. The genetic simplicity and vast arsenal of genetic tools available in Drosophila provides a unique opportunity to address questions regarding cancer initiation and progression that would be extremely challenging in other model systems. In this chapter we provide a historical overview of Drosophila as a model organism for cancer research, summarize the multitude of genetic tools available, offer a brief comparison between different model organisms and cell culture platforms used in cancer studies and briefly discuss some of the latest models and concepts in recent Drosophila cancer research.
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http://dx.doi.org/10.1007/978-3-030-23629-8_1DOI Listing
September 2019

CRL4Mahj E3 ubiquitin ligase promotes neural stem cell reactivation.

PLoS Biol 2019 06 6;17(6):e3000276. Epub 2019 Jun 6.

Neuroscience and Behavioural Disorders Programme, Duke-NUS Medical School, Singapore, Singapore.

The ability of neural stem cells (NSCs) to transit between quiescence and proliferation is crucial for brain development and homeostasis. Drosophila Hippo pathway maintains NSC quiescence, but its regulation during brain development remains unknown. Here, we show that CRL4Mahj, an evolutionarily conserved E3 ubiquitin ligase, is essential for NSC reactivation (exit from quiescence). We demonstrate that damaged DNA-binding protein 1 (DDB1) and Cullin4, two core components of Cullin4-RING ligase (CRL4), are intrinsically required for NSC reactivation. We have identified a substrate receptor of CRL4, Mahjong (Mahj), which is necessary and sufficient for NSC reactivation. Moreover, we show that CRL4Mahj forms a protein complex with Warts (Wts/large tumor suppressor [Lats]), a kinase of the Hippo signaling pathway, and Mahj promotes the ubiquitination of Wts. Our genetic analyses further support the conclusion that CRL4Mahj triggers NSC reactivation by inhibition of Wts. Given that Cullin4B mutations cause mental retardation and cerebral malformation, similar regulatory mechanisms may be applied to the human brain.
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http://dx.doi.org/10.1371/journal.pbio.3000276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6553684PMC
June 2019

Understanding human diseases using Drosophila.

J Genet Genomics 2019 04 26;46(4):155-156. Epub 2019 Apr 26.

Department of Biological Science, Florida State University, Tallahassee, FL, 32306, USA.

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http://dx.doi.org/10.1016/j.jgg.2019.04.001DOI Listing
April 2019

Oncogenic Notch Triggers Neoplastic Tumorigenesis in a Transition-Zone-like Tissue Microenvironment.

Dev Cell 2019 05 11;49(3):461-472.e5. Epub 2019 Apr 11.

Department of Biological Science, Florida State University, Tallahassee, FL 32306-4295, USA. Electronic address:

During the initial stages of tumorigenesis, the tissue microenvironment where the pro-tumor cells reside plays a crucial role in determining the fate of these cells. Transition zones, where two types of epithelial cells meet, are high-risk sites for carcinogenesis, but the underlying mechanism remains largely unclear. Here, we show that persistent upregulation of Notch signaling induces neoplastic tumorigenesis in a transition zone between the salivary gland imaginal ring cells and the giant cells in Drosophila larvae. In this region, local endogenous JAK-STAT and JNK signaling creates a tissue microenvironment that is susceptible to oncogenic-Notch-induced tumorigenesis, whereas the rest of the salivary gland imaginal ring is refractory to Notch-induced tumor transformation. JNK signaling activates a matrix metalloprotease (MMP1) to promote Notch-induced tumorigenesis at the transition zone. These findings illustrate the significance of local endogenous inflammatory signaling in primary tumor formation.
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http://dx.doi.org/10.1016/j.devcel.2019.03.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504601PMC
May 2019

Inhibition of Notch signaling by the p105 and p180 subunits of chromatin assembly factor 1 is required for follicle cell proliferation.

J Cell Sci 2019 01 25;132(2). Epub 2019 Jan 25.

Department of Biological Science, Florida State University, Tallahassee, Florida, USA

Chromatin assembly factor 1 (CAF1), a histone chaperone that mediates the deposition of histone H3/H4 onto newly synthesized DNA, is involved in Notch signaling activation during wing imaginal disc development. Here, we report another side of CAF1, wherein the subunits CAF1-p105 and CAF1-p180 (also known as CAF1-105 and CAF1-180, respectively) inhibit expression of Notch target genes and show this is required for proliferation of ovarian follicle cells. Loss-of-function of either CAF1-p105 or CAF1-p180 caused premature activation of Notch signaling reporters and early expression of the Notch target Hindsight (Hnt, also known as Pebbled), leading to Cut downregulation and inhibition of follicle cell mitosis. Our studies further show Notch is functionally responsible for these phenotypes observed in both the CAF1-p105- and CAF1-p180-deficient follicle cells. Moreover, we reveal that CAF1-p105- and CAF1-p180-dependent Cut expression is essential for inhibiting Hnt expression in follicle cells during their mitotic stage. These findings together indicate a novel negative-feedback regulatory loop between Cut and Hnt underlying CAF1-p105 and CAF-p180 regulation, which is crucial for follicle cell differentiation. In conclusion, our studies suggest CAF1 plays a dual role to sustain cell proliferation by positively or negatively regulating Notch signaling in a tissue-context-dependent manner.
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http://dx.doi.org/10.1242/jcs.224170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6362395PMC
January 2019

Germline silencing of UASt depends on the piRNA pathway.

J Genet Genomics 2018 05 9;45(5):273-276. Epub 2018 May 9.

Department of Biological Science, Florida State University, Tallahassee, FL 32306-4295, USA. Electronic address:

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http://dx.doi.org/10.1016/j.jgg.2018.04.005DOI Listing
May 2018

Serrate/Notch Signaling Regulates the Size of the Progenitor Cell Pool in Imaginal Rings.

Genetics 2018 07 17;209(3):829-843. Epub 2018 May 17.

Department of Biological Science, Florida State University, Tallahassee, Florida 32306-4295

imaginal rings are larval tissues composed of progenitor cells that are essential for the formation of adult foreguts, hindguts, and salivary glands. Specified from subsets of ectoderm in the embryo, imaginal ring cells are kept quiescent until midsecond larval instar, and undergo rapid proliferation during the third instar to attain adequate numbers of cells that will replace apoptotic larval tissues for adult organ formation. Here, we show that Notch signaling is activated in all three imaginal rings from middle embryonic stage to early pupal stage, and that Notch signaling positively controls cell proliferation in all three imaginal rings during the third larval instar. Our mutant clonal analysis, knockdown, and gain-of-function studies indicate that canonical Notch pathway components are involved in regulating the proliferation of these progenitor cells. Both -activation and -inhibition between the ligand and receptor control Notch activation in the imaginal ring. Serrate (Ser) is the ligand provided from neighboring imaginal ring cells that -activates Notch signaling, whereas both Ser and Delta (Dl) could -inhibit Notch activity when the ligand and the receptor are in the same cell. In addition, we show that Notch signaling expressed in middle embryonic and first larval stages is required for the initial size of imaginal rings. Taken together, these findings indicate that imaginal rings are excellent models to decipher how progenitor cell number and proliferation are developmentally regulated, and that Notch signaling in these imaginal tissues is the primary growth-promoting signal that controls the size of the progenitor cell pool.
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http://dx.doi.org/10.1534/genetics.118.300963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028248PMC
July 2018

Endoreplication: The Good, the Bad, and the Ugly.

Trends Cell Biol 2018 06 19;28(6):465-474. Epub 2018 Mar 19.

Department of Biological Science, Florida State University, Tallahassee, FL, USA. Electronic address:

To battle adverse internal and external conditions and maintain homeostasis, diploid organisms employ various cellular processes, such as proliferation and apoptosis. In some tissues, an alternative mechanism, endoreplication, is employed toward similar goals. Endoreplication is an evolutionarily conserved cell cycle program during which cells replicate their genomes without division, resulting in polyploid cells. Importantly, endoreplication is reported to be indispensable for normal development and organ formation across various organisms, from fungi to humans. In recent years, more attention has been drawn to delineating its connections to wound healing and tumorigenesis. In this Review, we discuss mechanisms of endoreplication and polyploidization, their essential and positive roles in normal development and tissue homeostasis, and the relationship between polyploidy and cancer.
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http://dx.doi.org/10.1016/j.tcb.2018.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5962415PMC
June 2018

Systematic analysis reveals tumor-enhancing and -suppressing microRNAs in epithelial tumors.

Oncotarget 2017 Dec 1;8(65):108825-108839. Epub 2017 Nov 1.

Department of Biological Science, Florida State University, Tallahassee, Florida, USA.

Despite their emergence as an important class of noncoding RNAs involved in cancer cell transformation, invasion, and migration, the precise role of microRNAs (miRNAs) in tumorigenesis remains elusive. To gain insights into how miRNAs contribute to primary tumor formation, we conducted an RNA sequencing (RNA-Seq) analysis of wing disc epithelial tumors induced by knockdown of a neoplastic tumor-suppressor gene (nTSG) (), combined with overexpression of an active form of oncogene ( ), and identified 51 mature miRNAs that changed significantly in tumorous discs. Followed by tumor enhancer and suppressor screens in sensitized genetic backgrounds, we identified 10 tumor-enhancing (TE) miRNAs and 11 tumor-suppressing (TS) miRNAs that contributed to the nTSG defect-induced tumorigenesis. Among these, four TE and three TS miRNAs have human homologs. From this study, we also identified 29 miRNAs that individually had no obvious role in enhancing or alleviating tumorigenesis despite their changed expression levels in nTSG tumors. This systematic analysis, which includes both RNA-Seq and functional studies, helps to categorize miRNAs into different groups based on their expression profile and functional relevance in epithelial tumorigenesis, whereas the evolutionarily conserved TE and TS miRNAs provide potential therapeutic targets for epithelial tumor treatment.
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http://dx.doi.org/10.18632/oncotarget.22226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5752484PMC
December 2017

HDAC6 Suppresses Age-Dependent Ectopic Fat Accumulation by Maintaining the Proteostasis of PLIN2 in Drosophila.

Dev Cell 2017 10 28;43(1):99-111.e5. Epub 2017 Sep 28.

Sino-French Hoffmann Institute, School of Basic Sciences, Guangzhou Medical University, Dongfengxi Road 195, Guangzhou 510182, China; State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, the Chinese Academy of Sciences, Datun Road 15, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100080, China; The Second Affiliated Hospital of Guangzhou Medical University, Changgangdong Road 250, Guangzhou 510260, China. Electronic address:

Age-dependent ectopic fat accumulation (EFA) in animals contributes to the progression of tissue aging and diseases such as obesity, diabetes, and cancer. However, the primary causes of age-dependent EFA remain largely elusive. Here, we characterize the occurrence of age-dependent EFA in Drosophila and identify HDAC6, a cytosolic histone deacetylase, as a suppressor of EFA. Loss of HDAC6 leads to significant age-dependent EFA, lipid composition imbalance, and reduced animal longevity on a high-fat diet. The EFA and longevity phenotypes are ameliorated by a reduction of the lipid-droplet-resident protein PLIN2. We show that HDAC6 is associated physically with the chaperone protein dHsc4/Hsc70 to maintain the proteostasis of PLIN2. These findings indicate that proteostasis collapse serves as an intrinsic cue to cause age-dependent EFA. Our study suggests that manipulation of proteostasis could be an alternative approach to the treatment of age-related metabolic diseases such as obesity and diabetes.
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http://dx.doi.org/10.1016/j.devcel.2017.09.001DOI Listing
October 2017

The Hox proteins Ubx and AbdA collaborate with the transcription pausing factor M1BP to regulate gene transcription.

EMBO J 2017 10 4;36(19):2887-2906. Epub 2017 Sep 4.

Aix Marseille Université, CNRS, IBDM, UMR 7288, Marseille, France

In metazoans, the pausing of RNA polymerase II at the promoter (paused Pol II) has emerged as a widespread and conserved mechanism in the regulation of gene transcription. While critical in recruiting Pol II to the promoter, the role transcription factors play in transitioning paused Pol II into productive Pol II is, however, little known. By studying how Hox transcription factors control transcription, we uncovered a molecular mechanism that increases productive transcription. We found that the Hox proteins AbdA and Ubx target gene promoters previously bound by the transcription pausing factor M1BP, containing paused Pol II and enriched with promoter-proximal Polycomb Group (PcG) proteins, yet lacking the classical H3K27me3 PcG signature. We found that AbdA binding to M1BP-regulated genes results in reduction in PcG binding, the release of paused Pol II, increases in promoter H3K4me3 histone marks and increased gene transcription. Linking transcription factors, PcG proteins and paused Pol II states, these data identify a two-step mechanism of Hox-driven transcription, with M1BP binding leading to Pol II recruitment followed by AbdA targeting, which results in a change in the chromatin landscape and enhanced transcription.
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http://dx.doi.org/10.15252/embj.201695751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5623858PMC
October 2017

Tissue-Intrinsic Tumor Hotspots: Terroir for Tumorigenesis.

Trends Cancer 2017 04 4;3(4):259-268. Epub 2017 Apr 4.

Department of Biological Science, Florida State University, Tallahassee, FL 32306-4295, USA. Electronic address:

Epithelial tissues are highly organized systems with a remarkable homeostatic ability to maintain morphology through regulation of cellular proliferation and tissue integrity. This robust self-organizing system is progressively disrupted during tumor development. Recent studies of conserved tumor-suppressor genes in Drosophila showed how protumor cells deviate from the robustly organized tissue microenvironment to take the first steps into becoming aggressive tumors. Here we review the 'tumor hotspot' hypothesis that explains how the tissue-intrinsic local microenvironment has a pivotal role in the initial stage of tumorigenesis in Drosophila epithelia and discuss comparable mechanisms in mammalian tissues.
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http://dx.doi.org/10.1016/j.trecan.2017.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5518481PMC
April 2017

The mA pathway facilitates sex determination in Drosophila.

Nat Commun 2017 07 4;8:15737. Epub 2017 Jul 4.

Department of Developmental Biology, Sloan-Kettering Institute, 1275 York Ave, Box 252, New York City, New York 10065, USA.

The conserved modification N-methyladenosine (mA) modulates mRNA processing and activity. Here, we establish the Drosophila system to study the mA pathway. We first apply miCLIP to map mA across embryogenesis, characterize its mA 'writer' complex, validate its YTH 'readers' CG6422 and YT521-B, and generate mutants in five mA factors. While mA factors with additional roles in splicing are lethal, mA-specific mutants are viable but present certain developmental and behavioural defects. Notably, mA facilitates the master female determinant Sxl, since multiple mA components enhance female lethality in Sxl sensitized backgrounds. The mA pathway regulates Sxl processing directly, since miCLIP data reveal Sxl as a major intronic mA target, and female-specific Sxl splicing is compromised in multiple mA pathway mutants. YT521-B is a dominant mA effector for Sxl regulation, and YT521-B overexpression can induce female-specific Sxl splicing. Overall, our transcriptomic and genetic toolkit reveals in vivo biologic function for the Drosophila mA pathway.
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http://dx.doi.org/10.1038/ncomms15737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5500889PMC
July 2017

Differential Regulation of Cyclin E by Yorkie-Scalloped Signaling in Organ Development.

G3 (Bethesda) 2017 03 10;7(3):1049-1060. Epub 2017 Mar 10.

Department of Biological Science, Florida State University, Tallahassee, Florida 32306-4295

Tissue integrity and homeostasis are accomplished through strict spatial and temporal regulation of cell growth and proliferation during development. Various signaling pathways have emerged as major growth regulators across metazoans; yet, how differential growth within a tissue is spatiotemporally coordinated remains largely unclear. Here, we report a role of a growth modulator Yorkie (), the homolog of Yes-associated protein (YAP), that differentially regulates its targets in wing imaginal discs; whereby Yki interacts with its transcriptional partner, Scalloped (), the homolog of the TEAD/TEF family transcription factor in mammals, to control an essential cell cycle regulator Cyclin E (CycE). Interestingly, when Yki was coexpressed with Fizzy-related (), a endocycle inducer and homolog of Cdh1 in mammals, surrounding hinge cells displayed larger nuclear size than distal pouch cells. The observed size difference is attributable to differential regulation of CycE, a target of Yki and Sd, the latter of which can directly bind to regulatory sequences, and is expressed only in the pouch region of the wing disc starting from the late second-instar larval stage. During earlier stages of larval development, when Sd expression was not detected in the wing disc, coexpression of Fzr and Yki did not cause size differences between cells along the proximal-distal axis of the disc. We show that ectopic CycE promoted cell proliferation and apoptosis, and inhibited transcriptional activity of Yki targets. These findings suggest that spatiotemporal expression of transcription factor Sd induces differential growth regulation by Yki during wing disc development, highlighting coordination between Yki and CycE to control growth and maintain homeostasis.
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http://dx.doi.org/10.1534/g3.117.039065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5345706PMC
March 2017

The SWI/SNF Complex Protein Snr1 Is a Tumor Suppressor in Imaginal Tissues.

Cancer Res 2017 02 6;77(4):862-873. Epub 2016 Dec 6.

Department of Biological Science, Florida State University, Tallahassee, Florida.

Components of the SWI/SNF chromatin-remodeling complex are among the most frequently mutated genes in various human cancers, yet only SMARCB1/hSNF5, a core member of the SWI/SNF complex, is mutated in malignant rhabdoid tumors (MRT). How SMARCB1/hSNF5 functions differently from other members of the SWI/SNF complex remains unclear. Here, we use imaginal epithelial tissues to demonstrate that Snr1, the conserved homolog of human SMARCB1/hSNF5, prevents tumorigenesis by maintaining normal endosomal trafficking-mediated signaling cascades. Removal of Snr1 resulted in neoplastic tumorigenic overgrowth in imaginal epithelial tissues, whereas depletion of any other members of the SWI/SNF complex did not induce similar phenotypes. Unlike other components of the SWI/SNF complex that were detected only in the nucleus, Snr1 was observed in both the nucleus and the cytoplasm. Aberrant regulation of multiple signaling pathways, including Notch, JNK, and JAK/STAT, was responsible for tumor progression upon -depletion. Our results suggest that the cytoplasmic Snr1 may play a tumor suppressive role in imaginal tissues, offering a foundation for understanding the pivotal role of SMARCB1/hSNF5 in suppressing MRT during early childhood. .
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http://dx.doi.org/10.1158/0008-5472.CAN-16-0963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885033PMC
February 2017

Epithelial Tumors Originate in Tumor Hotspots, a Tissue-Intrinsic Microenvironment.

PLoS Biol 2016 09 1;14(9):e1002537. Epub 2016 Sep 1.

Department of Biological Science, Florida State University, Tallahassee, Florida, United States of America.

Malignant tumors are caused by uncontrolled proliferation of transformed mutant cells that have lost the ability to maintain tissue integrity. Although a number of causative genetic backgrounds for tumor development have been discovered, the initial steps mutant cells take to escape tissue integrity and trigger tumorigenesis remain elusive. Here, we show through analysis of conserved neoplastic tumor-suppressor genes (nTSGs) in Drosophila wing imaginal disc epithelia that tumor initiation depends on tissue-intrinsic local cytoarchitectures, causing tumors to consistently originate in a specific region of the tissue. In this "tumor hotspot" where cells constitute a network of robust structures on their basal side, nTSG-deficient cells delaminate from the apical side of the epithelium and begin tumorigenic overgrowth by exploiting endogenous Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling activity. Conversely, in other regions, the "tumor coldspot" nTSG-deficient cells are extruded toward the basal side and undergo apoptosis. When the direction of delamination is reversed through suppression of RhoGEF2, an activator of the Rho family small GTPases, and JAK/STAT is activated ectopically in these coldspot nTSG-deficient cells, tumorigenesis is induced. These data indicate that two independent processes, apical delamination and JAK/STAT activation, are concurrently required for the initiation of nTSG-deficient-induced tumorigenesis. Given the conservation of the epithelial cytoarchitecture, tumorigenesis may be generally initiated from tumor hotspots by a similar mechanism.
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http://dx.doi.org/10.1371/journal.pbio.1002537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5008749PMC
September 2016

Maternal AP determinants in the Drosophila oocyte and embryo.

Wiley Interdiscip Rev Dev Biol 2016 09 2;5(5):562-81. Epub 2016 Jun 2.

Department of Biological Science, Florida State University, Tallahassee, FL, USA.

An animal embryo cannot initiate its journey of forming a new life on its own. It must rely on maternally provided resources and inputs to kick-start its developmental process. In Drosophila, the initial polarities of the embryo along both the anterior-posterior (AP) and dorsal-ventral (DV) axes are also specified by maternal determinants. Over the past several decades, genetic and molecular studies have identified and characterized such determinants, as well as the zygotic genetic regulatory networks that control patterning in the early embryo. Extensive studies of oogenesis have also led to a detailed knowledge of the cellular and molecular interactions that control the formation of a mature egg. Despite these efforts, oogenesis and embryogenesis have been studied largely as separate problems, except for qualitative aspects with regard to maternal regulation of the asymmetric localization of maternal determinants. Can oogenesis and embryogenesis be viewed from a unified perspective at a quantitative level, and can that improve our understanding of how robust embryonic patterning is achieved? Here, we discuss the basic knowledge of the regulatory mechanisms controlling oogenesis and embryonic patterning along the AP axis. We explore properties of the maternal Bicoid gradient in relation to embryo size in search for a unified framework for robust AP patterning. WIREs Dev Biol 2016, 5:562-581. doi: 10.1002/wdev.235 For further resources related to this article, please visit the WIREs website.
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http://dx.doi.org/10.1002/wdev.235DOI Listing
September 2016

The Ecdysone and Notch Pathways Synergistically Regulate Cut at the Dorsal-Ventral Boundary in Drosophila Wing Discs.

J Genet Genomics 2016 04 17;43(4):179-86. Epub 2016 Mar 17.

Department of Biological Science, Florida State University, Tallahassee, FL 32306-4295, USA. Electronic address:

Metazoan development requires coordination of signaling pathways to regulate patterns of gene expression. In Drosophila, the wing imaginal disc provides an excellent model for the study of how signaling pathways interact to regulate pattern formation. The determination of the dorsal-ventral (DV) boundary of the wing disc depends on the Notch pathway, which is activated along the DV boundary and induces the expression of the homeobox transcription factor, Cut. Here, we show that Broad (Br), a zinc-finger transcription factor, is also involved in regulating Cut expression in the DV boundary region. However, Br expression is not regulated by Notch signaling in wing discs, while ecdysone signaling is the upstream signal that induces Br for Cut upregulation. Also, we find that the ecdysone-Br cascade upregulates cut-lacZ expression, a reporter containing a 2.7 kb cut enhancer region, implying that ecdysone signaling, similar to Notch, regulates cut at the transcriptional level. Collectively, our findings reveal that the Notch and ecdysone signaling pathways synergistically regulate Cut expression for proper DV boundary formation in the wing disc. Additionally, we show br promotes Delta, a Notch ligand, near the DV boundary to suppress aberrant high Notch activity, indicating further interaction between the two pathways for DV patterning of the wing disc.
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http://dx.doi.org/10.1016/j.jgg.2016.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5391978PMC
April 2016

RNA helicase Belle/DDX3 regulates transgene expression in Drosophila.

Dev Biol 2016 Apr 18;412(1):57-70. Epub 2016 Feb 18.

Department of Biological Science, Florida State University, Tallahassee, FL, USA. Electronic address:

Belle (Bel), the Drosophila homolog of the yeast DEAD-box RNA helicase DED1 and human DDX3, has been shown to be required for oogenesis and female fertility. Here we report a novel role of Bel in regulating the expression of transgenes. Abrogation of Bel by mutations or RNAi induces silencing of a variety of P-element-derived transgenes. This silencing effect depends on downregulation of their RNA levels. Our genetic studies have revealed that the RNA helicase Spindle-E (Spn-E), a nuage RNA helicase that plays a crucial role in regulating RNA processing and PIWI-interacting RNA (piRNA) biogenesis in germline cells, is required for loss-of-bel-induced transgene silencing. Conversely, Bel abrogation alleviates the nuage-protein mislocalization phenotype in spn-E mutants, suggesting a competitive relationship between these two RNA helicases. Additionally, disruption of the chromatin remodeling factor Mod(mdg4) or the microRNA biogenesis enzyme Dicer-1 (Dcr-1) also alleviates the transgene-silencing phenotypes in bel mutants, suggesting the involvement of chromatin remodeling and microRNA biogenesis in loss-of-bel-induced transgene silencing. Finally we show that genetic inhibition of Bel function leads to de novo generation of piRNAs from the transgene region inserted in the genome, suggesting a potential piRNA-dependent mechanism that may mediate transgene silencing as Bel function is inhibited.
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http://dx.doi.org/10.1016/j.ydbio.2016.02.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4814335PMC
April 2016

Automatic stage identification of Drosophila egg chamber based on DAPI images.

Sci Rep 2016 Jan 6;6:18850. Epub 2016 Jan 6.

Department of Biological Science, Florida State University, Tallahassee, FL 32306-4370, USA.

The Drosophila egg chamber, whose development is divided into 14 stages, is a well-established model for developmental biology. However, visual stage determination can be a tedious, subjective and time-consuming task prone to errors. Our study presents an objective, reliable and repeatable automated method for quantifying cell features and classifying egg chamber stages based on DAPI images. The proposed approach is composed of two steps: 1) a feature extraction step and 2) a statistical modeling step. The egg chamber features used are egg chamber size, oocyte size, egg chamber ratio and distribution of follicle cells. Methods for determining the on-site of the polytene stage and centripetal migration are also discussed. The statistical model uses linear and ordinal regression to explore the stage-feature relationships and classify egg chamber stages. Combined with machine learning, our method has great potential to enable discovery of hidden developmental mechanisms.
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http://dx.doi.org/10.1038/srep18850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4702167PMC
January 2016

Ligand-Independent Mechanisms of Notch Activity.

Trends Cell Biol 2015 Nov 1;25(11):697-707. Epub 2015 Oct 1.

Department of Biological Science, Florida State University, Tallahassee, FL 32306-4295, USA. Electronic address:

Interaction between the Notch receptor and Delta-Serrate-Lag2 (DSL) ligands is generally deemed to be the starting point of the Notch signaling cascade, after which, Notch is cleaved and the intracellular domain acts as a transcriptional coactivator. By contrast, Notch protein can become activated independent of ligand stimulus through recently identified endosomal trafficking routes as well as through aberrant regulation of Notch components during Notch trafficking, ubiquitination, and degradation. In this review, we summarize genes implicated in ligand-independent Notch activity and remark on the mechanisms by which this process could occur.
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http://dx.doi.org/10.1016/j.tcb.2015.07.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4628868PMC
November 2015

Analysis of Cell Cycle Switches in Drosophila Oogenesis.

Methods Mol Biol 2015 ;1328:207-16

Department of Biological Science, Florida State University, Tallahassee, FL, USA.

The study of Drosophila oogenesis provides invaluable information about signaling pathway regulation and cell cycle programming. During Drosophila oogenesis, a string of egg chambers in each ovariole progressively develops toward maturity. Egg chamber development consists of 14 stages. From stage 1 to stage 6 (mitotic cycle), main-body follicle cells undergo mitotic divisions. From stage 7 to stage 10a (endocycle), follicle cells cease mitosis but continue three rounds of endoreduplication. From stage 10b to stage 13 (gene amplification), instead of whole genome duplication, follicle cells selectively amplify specific genomic regions, mostly for chorion production. So far, Drosophila oogenesis is one of the most well studied model systems used to understand cell cycle switches, which furthers our knowledge about cell cycle control machinery and sheds new light on potential cancer treatments. Here, we give a brief summary of cell cycle switches, the associated signaling pathways and factors, and the detailed experimental procedures used to study the cell cycle switches.
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http://dx.doi.org/10.1007/978-1-4939-2851-4_15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455776PMC
May 2016

A large-scale in vivo RNAi screen to identify genes involved in Notch-mediated follicle cell differentiation and cell cycle switches.

Sci Rep 2015 Jul 24;5:12328. Epub 2015 Jul 24.

Department of Biological Science, Florida State University, Tallahassee, FL 32306-4370, USA.

During Drosophila oogenesis, follicle cells sequentially undergo three distinct cell-cycle programs: the mitotic cycle, endocycle, and gene amplification. Notch signaling plays a central role in regulating follicle-cell differentiation and cell-cycle switches; its activation is essential for the mitotic cycle/endocycle (M/E) switch. Cut, a linker between Notch signaling and cell-cycle regulators, is specifically downregulated by Notch during the endocycle stage. To determine how signaling pathways coordinate during the M/E switch and to identify novel genes involved in follicle cell differentiation, we performed an in vivo RNAi screen through induced knockdown of gene expression and examination of Cut expression in follicle cells. We screened 2205 RNAi lines and found 33 genes regulating Cut expression during the M/E switch. These genes were confirmed with the staining of two other Notch signaling downstream factors, Hindsight and Broad, and validated with multiple independent RNAi lines. We applied gene ontology software to find enriched biological meaning and compared our results with other publications to find conserved genes across tissues. Specifically, we found earlier endocycle entry in anterior follicle cells than those in the posterior, identified that the insulin-PI3K pathway participates in the precise M/E switch, and suggested Nejire as a cofactor of Notch signaling during oogenesis.
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http://dx.doi.org/10.1038/srep12328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4513280PMC
July 2015
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