Donald Fox

Overview:

Please visit www.foxlabduke.com

Research overview:
Extreme genome variation in organ development and repair.

The genome provides the blueprint for life. To achieve specialized cell or tissue function, specific genome features can be altered or exploited in extreme ways. My research program focuses on two such extreme genome variations: polyploidy and codon usage bias (defined below). In multicellular organisms with specialized organ systems, the function and regulation of these two extreme genome variations remains largely mysterious. We established accessible models where these two extreme genome variations impact cell and tissue biology.

1) Polyploidy. In numerous tissues or whole organisms, one nucleus can contain tens to thousands of genomes. Such whole genome duplication, or polyploidy, massively alters the transcriptome, proteome, and metabolome. We are only just beginning to understand the purposes of polyploidy in three crucial settings: organ development, organ repair, and ectopic polyploidy that can contribute to disease. My laboratory established accessible models of these processes using Drosophila. Our goal is to uncover fundamental functions and distinguishing regulation of polyploidy.

2) Codon usage bias. The genetic code is redundant, with 61 codons encoding 20 amino acids. Despite this redundancy, synonymous codons encoding the same amino acid occur at varying frequencies. “Rare” codons occur least often while other “common” codons occur most often. Altering codon bias across evolution affects mRNA translation and has biological consequences. The impact of codon bias on tissue-specific differentiation has been largely unexplored. In Drosophila, we discovered that the ability to express genes enriched in rare codons is a defining characteristic of at least two specific organs. We are uncovering evidence that these organs express rare codon-enriched genes to achieve cell and tissue-specific identity. We are thus well-poised to define, for the first time, the role of codon bias in tissue-specific development.

Positions:

Associate Professor of Pharmacology & Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Assistant Professor in Cell Biology

Cell Biology
School of Medicine

Associate of the Duke Initiative for Science & Society

Duke Science & Society
Institutes and Provost's Academic Units

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Affiliate of the Regeneration Next Initiative

Regeneration Next Initiative
School of Medicine

Education:

B.S. 2000

College of William and Mary

Ph.D. 2006

University of North Carolina - Chapel Hill

Grants:

Hypertrophy vs. Proliferation Following Tissue Injury: A Drosophila Model

Administered By
Pharmacology & Cancer Biology
Awarded By
American Heart Association
Role
Principal Investigator
Start Date
End Date

Impact of polyploidy on establishing an HIV-1 reservoir in the kidney

Administered By
Medicine, Infectious Diseases
Awarded By
University of Alabama at Birmingham
Role
Principal Investigator
Start Date
End Date

Par-4 Regulation and Function in Breast Cancer Dormancy and Recurrence

Administered By
Pharmacology & Cancer Biology
Awarded By
National Institutes of Health
Role
Co Investigator
Start Date
End Date

Publications:

Polyploidy: A Biological Force From Cells to Ecosystems.

Polyploidy, resulting from the duplication of the entire genome of an organism or cell, greatly affects genes and genomes, cells and tissues, organisms, and even entire ecosystems. Despite the wide-reaching importance of polyploidy, communication across disciplinary boundaries to identify common themes at different scales has been almost nonexistent. However, a critical need remains to understand commonalities that derive from shared polyploid cellular processes across organismal diversity, levels of biological organization, and fields of inquiry - from biodiversity and biocomplexity to medicine and agriculture. Here, we review the current understanding of polyploidy at the organismal and suborganismal levels, identify shared research themes and elements, and propose new directions to integrate research on polyploidy toward confronting interdisciplinary grand challenges of the 21st century.
Authors
Fox, DT; Soltis, DE; Soltis, PS; Ashman, T-L; Van de Peer, Y
MLA Citation
Fox, Donald T., et al. “Polyploidy: A Biological Force From Cells to Ecosystems.Trends Cell Biol, vol. 30, no. 9, Sept. 2020, pp. 688–94. Pubmed, doi:10.1016/j.tcb.2020.06.006.
URI
https://scholars.duke.edu/individual/pub1450769
PMID
32646579
Source
pubmed
Published In
Trends Cell Biol
Volume
30
Published Date
Start Page
688
End Page
694
DOI
10.1016/j.tcb.2020.06.006

Model systems for regeneration: Drosophila.

Drosophila melanogaster has historically been a workhorse model organism for studying developmental biology. In addition, Drosophila is an excellent model for studying how damaged tissues and organs can regenerate. Recently, new precision approaches that enable both highly targeted injury and genetic manipulation have accelerated progress in this field. Here, we highlight these techniques and review examples of recently discovered mechanisms that regulate regeneration in Drosophila larval and adult tissues. We also discuss how, by applying these powerful approaches, studies of Drosophila can continue to guide the future of regeneration research.
Authors
Fox, DT; Cohen, E; Smith-Bolton, R
MLA Citation
Fox, Donald T., et al. “Model systems for regeneration: Drosophila.Development, vol. 147, no. 7, Apr. 2020. Pubmed, doi:10.1242/dev.173781.
URI
https://scholars.duke.edu/individual/pub1436714
PMID
32253254
Source
pubmed
Published In
Development
Volume
147
Published Date
DOI
10.1242/dev.173781

Exploiting codon usage identifies RpS21 as an in vivo signal strength-dependent Ras/MAPK regulator

ABSTRACT Signal transduction pathways are intricately fine-tuned to accomplish diverse biological processes. An example is the conserved Ras/mitogen-activated-protein-kinase (MAPK) pathway, which exhibits context-dependent signaling output dynamics and regulation. Here, by altering codon usage as a novel platform to control signaling output, we screened the Drosophila genome for modifiers specific to either weak or strong Ras-driven eye phenotypes. We mapped the underlying gene from one modifier to the ribosomal gene RpS21 . RpS21 preferentially influences weak Ras/MAPK signaling outputs, and negatively regulates Ras/MAPK in multiple cell/tissue and signaling settings. In turn, MAPK signaling may regulate its own negative feedback by promoting RpS21 expression. These data show that codon usage manipulation can identify output-specific signaling regulators, and identify RpS21 as an in vivo Ras/MAPK phenotypic regulator.
Authors
Sawyer, J; Kabiri, Z; Montague, R; Paramore, S; Cohen, E; Zaribafzadeh, H; Counter, C; Fox, D
MLA Citation
URI
https://scholars.duke.edu/individual/pub1404008
Source
epmc
Published Date
DOI
10.1101/650630

Polyploidy and Mitotic Cell Death Are Two Distinct HIV-1 Vpr-Driven Outcomes in Renal Tubule Epithelial Cells.

Prior studies have found that HIV, through the Vpr protein, promotes genome reduplication (polyploidy) in infection-surviving epithelial cells within renal tissue. However, the temporal progression and molecular regulation through which Vpr promotes polyploidy have remained unclear. Here we define a sequential progression to Vpr-mediated polyploidy in human renal tubule epithelial cells (RTECs). We found that as in many cell types, Vpr first initiates G2 cell cycle arrest in RTECs. We then identified a previously unreported cascade of Vpr-dependent events that lead to renal cell survival and polyploidy. Specifically, we found that a fraction of G2-arrested RTECs reenter the cell cycle. Following this cell cycle reentry, two distinct outcomes occur. Cells that enter complete mitosis undergo mitotic cell death due to extra centrosomes and aberrant division. Conversely, cells that abort mitosis undergo endoreplication to become polyploid. We further show that multiple small-molecule inhibitors of the phosphatidylinositol 3-kinase-related kinase (PIKK) family, including those that target ATR, ATM, and mTOR, indirectly prevent Vpr-mediated polyploidy by preventing G2 arrest. In contrast, an inhibitor that targets DNA-dependent protein kinase (DNA-PK) specifically blocks the Vpr-mediated transition from G2 arrest to polyploidy. These findings outline a temporal, molecularly regulated path to polyploidy in HIV-positive renal cells.IMPORTANCE Current cure-focused efforts in HIV research aim to elucidate the mechanisms of long-term persistence of HIV in compartments. The kidney is recognized as one such compartment, since viral DNA and mRNA persist in the renal tissues of HIV-positive patients. Further, renal disease is a long-term comorbidity in the setting of HIV. Thus, understanding the regulation and impact of HIV infection on renal cell biology will provide important insights into this unique HIV compartment. Our work identifies mechanisms that distinguish between HIV-positive cell survival and death in a known HIV compartment, as well as pharmacological agents that alter these outcomes.
Authors
Payne, EH; Ramalingam, D; Fox, DT; Klotman, ME
MLA Citation
Payne, Emily H., et al. “Polyploidy and Mitotic Cell Death Are Two Distinct HIV-1 Vpr-Driven Outcomes in Renal Tubule Epithelial Cells.J Virol, vol. 92, no. 2, Jan. 2018. Pubmed, doi:10.1128/JVI.01718-17.
URI
https://scholars.duke.edu/individual/pub1284379
PMID
29093088
Source
pubmed
Published In
J Virol
Volume
92
Published Date
DOI
10.1128/JVI.01718-17

Rho1 regulates Drosophila adherens junctions independently of p120ctn.

During animal development, adherens junctions (AJs) maintain epithelial cell adhesion and coordinate changes in cell shape by linking the actin cytoskeletons of adjacent cells. Identifying AJ regulators and their mechanisms of action are key to understanding the cellular basis of morphogenesis. Previous studies linked both p120catenin and the small GTPase Rho to AJ regulation and revealed that p120 may negatively regulate Rho. Here we examine the roles of these candidate AJ regulators during Drosophila development. We found that although p120 is not essential for development, it contributes to morphogenesis efficiency, clarifying its role as a redundant AJ regulator. Rho has a dynamic localization pattern throughout ovarian and embryonic development. It preferentially accumulates basally or basolaterally in several tissues, but does not preferentially accumulate in AJs. Further, Rho1 localization is not obviously altered by loss of p120 or by reduction of core AJ proteins. Genetic and cell biological tests suggest that p120 is not a major dose-sensitive regulator of Rho1. However, Rho1 itself appears to be a regulator of AJs. Loss of Rho1 results in ectopic accumulation of cytoplasmic DE-cadherin, but ectopic cadherin does not accumulate with its partner Armadillo. These data suggest Rho1 regulates AJs during morphogenesis, but this regulation is p120 independent.
Authors
Fox, DT; Homem, CCF; Myster, SH; Wang, F; Bain, EE; Peifer, M
MLA Citation
Fox, Donald T., et al. “Rho1 regulates Drosophila adherens junctions independently of p120ctn.Development, vol. 132, no. 21, Nov. 2005, pp. 4819–31. Pubmed, doi:10.1242/dev.02056.
URI
https://scholars.duke.edu/individual/pub771699
PMID
16207756
Source
pubmed
Published In
Development (Cambridge, England)
Volume
132
Published Date
Start Page
4819
End Page
4831
DOI
10.1242/dev.02056

Research Areas:

Aneuploidy
Cell Cycle
Gene Dosage
Genome
Genomic Instability
Image Processing, Computer-Assisted
Microscopy, Confocal
Polyploidy
Transcriptome