Todd Nystul, PhD

Associate Professor
Department of Anatomy
+1 415 476-6883

Background:

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?

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.

Research Summary: 
Epithelial stem cells and cancer

Websites

Publications: 

Wingless promotes EGFR signaling in follicle stem cells to maintain self-renewal.

Development (Cambridge, England)

Kim-Yip RP, Nystul TG

Cell fate decisions: emerging roles for metabolic signals and cell morphology.

EMBO reports

Tatapudy S, Aloisio F, Barber D, Nystul T

Methods for Imaging Intracellular pH of the Follicle Stem Cell Lineage in Live Drosophila Ovarian Tissue.

Journal of visualized experiments : JoVE

Tatapudy S, Benitez M, Nystul T

Increased intracellular pH is necessary for adult epithelial and embryonic stem cell differentiation.

The Journal of cell biology

Ulmschneider B, Grillo-Hill BK, Benitez M, Azimova DR, Barber DL, Nystul TG

Enhancer-trap flippase lines for clonal analysis in the Drosophila ovary.

G3 (Bethesda, Md.)

Huang P, Sahai-Hernandez P, Bohm RA, Welch WP, Zhang B, Nystul T

Drosophila models of epithelial stem cells and their niches.

Wiley interdisciplinary reviews. Developmental biology

Sahai-Hernandez P, Castanieto A, Nystul TG

The carnegie protein trap library: a versatile tool for Drosophila developmental studies.

Genetics

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

Nystul TG, Spradling AC

Buying time in suspended animation.

Scientific American

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

Nystul TG, Roth MB

Suspended animation in C. elegans requires the spindle checkpoint.

Science (New York, N.Y.)

Nystul TG, Goldmark JP, Padilla PA, Roth MB