Todd Nystul, PhD
Professor
Anatomy
School of Medicine
Background:
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The follicular epithelium in the Drosophila ovary is an ideal model for the study of epithelial biology. It possesses many classical epithelial features, such as a columnar cell shape, apical/basal polarity, and canonical cell adhesion complexes, and yet is a relatively simple tissue and is highly tractable for molecular and cell biological analysis. Combined with the powerful genetic tools available in Drosophila, this allows us to address questions in epithelial stem cell and tissue biology with single-cell resolution in the natural, in vivo context.
Major Goals: Our laboratory uses the Drosophila ovary as a model for studying the fundamental properties of epithelial stem cells, their associated niche, and the connection between epithelial stem cells and cancer. We are interested in questions such as:
1. How is stem cell fate maintained within a dynamic epithelial tissue? 2. What is the nature of the epithelial stem cell niche? 3. What is the role of epithelial stem cells in normal reproductive physiology? 4. Do stem cell defects underlie epithelial cancers and what can studies of epithelial stem cells teach us about the earliest steps in cancer formation? 5. How are stem cell function and tissue homology affected by aging?
Ongoing research:
Identifying Stem Cells and their Niche
Although adult stem cells are believed to reside in distinct microenvironments, or niches, that function to regulate stem cell behavior, niches have been hard to study because of the difficulty of precisely identifying the stem cells in most tissues. However, we have developed a set of criteria that facilitates reliable identification of the epithelial follicle stem cells (FSCs) in the Drosophila ovary and we are now mapping their interactions with neighboring cells to better understand the nature of the FSC niche. Surprisingly, we have found that the FSC niche appears much more dynamic than the few previously characterized niches. We are using lineage analysis to follow FSC behavior, track the patterns of FSC daughter cell migration and differentiation, and investigate relevant gene function.
Epithelial Stem Cell Genetics
The wnt/wingless, hedgehog, BMP and Notch signaling pathways are all important for FSC function and early epithelial development but little is known about where in the process these signals exert their effects or how they are coordinated to produce a functional, healthy epithelium. We are investigating the function of key signaling components at specific steps in early follicle formation to map the contributions of these pathways to FSC function and follicle formation. In addition, we are interested in the role that misregulation of signaling in the ovarian epithelial cells plays in ovarian cancer. We are now investigating the interaction between the wnt pathway and other putative ovarian cancer genes in follicle cells as well as screening for markers that identify pre-tumorous cells to better understand the early steps leading to hyperplasia. Through collaboration with our colleagues in the Center for Reproductive Sciences, we will be able to test whether gene interactions and markers that we identify in the fly ovary will also be present in mammalian model systems and human tissues. To identify additional genes that are required for proper FSC function, we screened through a collection of over 600 lines bearing lethal mutations. We have identified several mutants with a follicle stem cell phenotype including ones that accelerate the rate of stem cell loss; confer a “hyper-competitive” stem cell replacement phenotype; and/or cause over-proliferation, perhaps modeling a precancerous state.
Epithelial Stem Cells and Oogenesis Oogenesis is well conserved from flies to mammals and studies of the Drosophila ovary have provided valuable insight into the process of female reproduction. Our work on the characterization of the follicle stem cells and their associated niche provides an opportunity to use the fly ovary as a model of follicle formation. By studying the lineage just downstream of the FSCs, we found that FSCs produce “pre-follicle cells” that are developmental intermediates between the FSCs and the polarized epithelium. Follicle formation begins when a newly formed germline cyst moves past the FSC niche and contacts these pre-follicle cells. We found that a Delta signal from the germline activates Notch in some pre-follicle cells, inducing them to migrate along the anterior fact of the cyst toward the opposite niche. Other pre-follicle cells that do not receive the signal instead migrate away from the niche toward the posterior, directly into the polarized epithelium. We are now studying how these and other cellular events lead to the formation of a new follicle during normal oogenesis.
Interests
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- Drosophila
- epithelia
- Stem cells
- aging
Grants and Projects
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- Cell Fate Decisions in Epithelial Stem Cell Lineages, NIH, 2020-2025
- Modeling epithelial stem cell competition in a dynamic drosophila ovarian niche, NIH, 2011-2020
- Regulation of Epithelial Plasticity, NIH, 2015-2019
- Models for studying of the role of stem cell competition in field cancerization, NIH, 2012-2015
Publications (38)
Top publication keywords:
Hedgehog ProteinsUbiquitin-Conjugating EnzymesOogenesisOvaryEpithelial CellsDrosophila ProteinsStem CellsSmoothened ReceptorDrosophilaErbB ReceptorsReceptors, Invertebrate PeptideOvarian FollicleWnt1 ProteinStem Cell NicheDrosophila melanogaster
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A high-throughput method for quantifying Drosophila fecundity.
bioRxiv : the preprint server for biology 2024 Gomez A, Gonzalez S, Oke A, Luo J, Duong JB, Esquerra RM, Zimmerman T, Capponi S, Fung JC, Nystul TG -
Single-cell RNA sequencing identifies eggplant as a regulator of germ cell development in Drosophila.
EMBO reports 2023 Sun Z, Nystul TG, Zhong G -
Intracellular pH dynamics regulates intestinal stem cell lineage specification.
Nature communications 2023 Liu Y, Reyes E, Castillo-Azofeifa D, Klein OD, Nystul T, Barber DL -
A DLG1-ARHGAP31-CDC42 axis is essential for the intestinal stem cell response to fluctuating niche Wnt signaling.
Cell stem cell 2023 Castillo-Azofeifa D, Wald T, Reyes EA, Gallagher A, Schanin J, Vlachos S, Lamarche-Vane N, Bomidi C, Blutt S, Estes MK, Nystul T, Klein OD -
Preparation of Drosophila Ovarioles for Single-Cell RNA Sequencing.
Methods in molecular biology (Clifton, N.J.) 2023 Meyer N, Peralta J, Nystul T
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Fly Cell Atlas: A single-nucleus transcriptomic atlas of the adult fruit fly.
Science (New York, N.Y.) 2022 Li H, Janssens J, De Waegeneer M, Kolluru SS, Davie K, Gardeux V, Saelens W, David FPA, Brbic M, Spanier K, Leskovec J, McLaughlin CN, Xie Q, Jones RC, Brueckner K, Shim J, Tattikota SG, Schnorrer F, … -
Distinct roles of Bendless in regulating FSC niche competition and daughter cell differentiation.
Development (Cambridge, England) 2021 Tatapudy S, Peralta J, Nystul T -
Author Correction: A single-cell atlas and lineage analysis of the adult Drosophila ovary.
Nature communications 2021 Rust K, Byrnes LE, Yu KS, Park JS, Sneddon JB, Tward AD, Nystul TG -
A single-cell atlas and lineage analysis of the adult Drosophila ovary.
Nature communications 2020 Rust K, Byrnes LE, Yu KS, Park JS, Sneddon JB, Tward AD, Nystul TG -
Signal transduction in the early Drosophila follicle stem cell lineage.
Current opinion in insect science 2020 Rust K, Nystul T -
The follicle epithelium in the Drosophila ovary is maintained by a small number of stem cells.
eLife 2019 Fadiga J, Nystul TG -
Drosophila anion exchanger 2 is required for proper ovary development and oogenesis.
Developmental biology 2019 Benitez M, Tatapudy S, Liu Y, Barber DL, Nystul TG -
Wingless promotes EGFR signaling in follicle stem cells to maintain self-renewal.
Development (Cambridge, England) 2018 Kim-Yip RP, Nystul TG -
Cell fate decisions: emerging roles for metabolic signals and cell morphology.
EMBO reports 2017 Tatapudy S, Aloisio F, Barber D, Nystul T -
Methods for Imaging Intracellular pH of the Follicle Stem Cell Lineage in Live <em>Drosophila</em> Ovarian Tissue.
Journal of Visualized Experiments 2017 Sumitra Tatapudy, Marimar Benitez, Todd Nystul -
Methods for Imaging Intracellular pH of the Follicle Stem Cell Lineage in Live Drosophila Ovarian Tissue.
Journal of visualized experiments : JoVE 2017 Tatapudy S, Benitez M, Nystul T -
Neutral Competition for Drosophila Follicle and Cyst Stem Cell Niches Requires Vesicle Trafficking Genes.
Genetics 2017 Cook MS, Cazin C, Amoyel M, Yamamoto S, Bach E, Nystul T -
Phosphorylated Groucho delays differentiation in the follicle stem cell lineage by providing a molecular memory of EGFR signaling in the niche.
Development (Cambridge, England) 2016 Johnston MJ, Bar-Cohen S, Paroush Z, Nystul TG -
Increased intracellular pH is necessary for adult epithelial and embryonic stem cell differentiation.
The Journal of cell biology 2016 Ulmschneider B, Grillo-Hill BK, Benitez M, Azimova DR, Barber DL, Nystul TG -
A Pak-regulated cell intercalation event leading to a novel radial cell polarity is involved in positioning of the follicle stem cell niche in the Drosophila ovary.
Development (Cambridge, England) 2015 Vlachos S, Jangam S, Conder R, Chou M, Nystul T, Harden N -
EGFR signaling promotes self-renewal through the establishment of cell polarity in Drosophila follicle stem cells.
eLife 2014 Castanieto A, Johnston MJ, Nystul TG -
Enhancer-trap flippase lines for clonal analysis in the Drosophila ovary.
G3 (Bethesda, Md.) 2014 Huang P, Sahai-Hernandez P, Bohm RA, Welch WP, Zhang B, Nystul T -
Basolateral junction proteins regulate competition for the follicle stem cell niche in the Drosophila ovary.
PloS one 2014 Kronen MR, Schoenfelder KP, Klein AM, Nystul TG -
A dynamic population of stromal cells contributes to the follicle stem cell niche in the Drosophila ovary.
Development (Cambridge, England) 2013 Sahai-Hernandez P, Nystul TG -
Advanced Techniques for Cell Lineage Labelling in Drosophila.
eLS 2012 Yassi Hafezi, Todd G Nystul -
Drosophila models of epithelial stem cells and their niches.
Wiley interdisciplinary reviews. Developmental biology 2012 Sahai-Hernandez P, Castanieto A, Nystul TG -
Regulation of epithelial stem cell replacement and follicle formation in the Drosophila ovary.
Genetics 2009 Nystul T, Spradling A -
Stem cells and their niches: integrated units that maintain Drosophila tissues.
Cold Spring Harbor symposia on quantitative biology 2008 Spradling AC, Nystul T, Lighthouse D, Morris L, Fox D, Cox R, Tootle T, Frederick R, Skora A -
An epithelial niche in the Drosophila ovary undergoes long-range stem cell replacement.
Cell stem cell 2007 Nystul T, Spradling A -
The carnegie protein trap library: a versatile tool for Drosophila developmental studies.
Genetics 2006 Buszczak M, Paterno S, Lighthouse D, Bachman J, Planck J, Owen S, Skora AD, Nystul TG, Ohlstein B, Allen A, Wilhelm JE, Murphy TD, Levis RW, Matunis E, Srivali N, Hoskins RA, Spradling AC -
Breaking out of the mold: diversity within adult stem cells and their niches.
Current opinion in genetics & development 2006 Nystul TG, Spradling AC -
Multiple types of niche control stem cells in drosophila adults.
Developmental Biology 2006 Allan Spradling, Benjamin Ohlstein, Michael Buszczak, Todd Nystul, Lucy Morris, Eva Decotto -
Buying time in suspended animation.
Scientific American 2005 Roth MB, Nystul T -
Carbon monoxide-induced suspended animation protects against hypoxic damage in Caenorhabditis elegans.
Proceedings of the National Academy of Sciences of the United States of America 2004 Nystul TG, Roth MB -
Suspended animation in C. elegans requires the spindle checkpoint.
Science (New York, N.Y.) 2003 Nystul TG, Goldmark JP, Padilla PA, Roth MB -
Dephosphorylation of cell cycle-regulated proteins correlates with anoxia-induced suspended animation in Caenorhabditis elegans.
Molecular biology of the cell 2002 Padilla PA, Nystul TG, Zager RA, Johnson AC, Roth MB -
Giardia lamblia expresses a proteobacterial-like DnaK homolog.
Molecular biology and evolution 2001 Morrison HG, Roger AJ, Nystul TG, Gillin FD, Sogin ML -
Novel protein-disulfide isomerases from the early-diverging protist Giardia lamblia.
The Journal of biological chemistry 1999 Knodler LA, Noiva R, Mehta K, McCaffery JM, Aley SB, Svärd SG, Nystul TG, Reiner DS, Silberman JD, Gillin FD