The asymmetric self-renewal divisions of adult stem cells underlie the continued homeostasis of many tissues of the body. Most, if not all, stem cells are present in a microenvironment, called a niche that provides three conditions necessary for long-term stem cell maintenance. Adhesion between the niche cell and the stem cell anchors the stem cell within the niche. Intercellular signals from the niche maintain the stem cell in an undifferentiated state. Lastly, the niche has the capability to set up an intrinsic polarity within the stem cell to aid its asymmetric self-renewal divisions. An understanding of these interactions in an in vivo environment is essential prior to the use of stem cells for therapeutic purposes. The female germ line of the fruit fly Drosophila melanogaster is one of the preeminent systems for the study of stem cell niche interactions. The Germline Stem Cells (GSCs) are located at the anterior tip of each ovariole, adjacent to somatic cap cells that form the niche. Each GSC divides with an invariant plane of division to produce one daughter that stays in the niche and remains a GSC and a second daughter, a Cystoblast (CB), which leaves the niche and ultimately produces an oocyte. The GSCs are anchored to the cap cells by adherens junctions. Moreover, Bone Morphogenetic Protein (BMP) family members act as intercellular signals necessary for GSC maintenance. BMP signaling is high in GSCs, low in CBs, and absent from all CB progeny. This proposal tests the hypothesis that interactions between the cap cells and the GSCs set up an intrinsic polarity within the GSC that is manifest as an asymmetric activation of the small GTPase Rac at the GSC cap cell interface. Preliminary data suggest that locally activated Rac both controls the plane of division of the GSC and promotes BMP signaling within the GSC. The three specific aims in the proposal are designed to provide a molecular framework to understand how a cellular asymmetry within a stem cell can cooperate with an extracellular signal required for stem cell maintenance to ensure the robust pattern of asymmetric self-renewal divisions necessary for continued stem cell maintenance. These data should provide an intellectual framework to examine the mechanisms underlying the self-renewal divisions of vertebrate adult stem cells. Project Narrative. A stem cell normally divides to produce one cell like itself and one cell that differentiates into a particular tissue type, such as blood, skin or hair. The proposal seeks to understand how the interaction between a stem cell and its surrounding environment can influence the pattern of stem cell division. This knowledge could be very useful in attempts to use stem cells to heal injury or cure disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM078481-03S1
Application #
8003080
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Haynes, Susan R
Project Start
2010-01-08
Project End
2010-12-31
Budget Start
2010-01-08
Budget End
2010-12-31
Support Year
3
Fiscal Year
2010
Total Cost
$55,207
Indirect Cost
Name
University of Chicago
Department
Genetics
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Gavin-Smyth, Jackie; Wang, Yu-Chiun; Butler, Ian et al. (2013) A genetic network conferring canalization to a bistable patterning system in Drosophila. Curr Biol 23:2296-302
Lu, Wen; Casanueva, M Olivia; Mahowald, Anthony P et al. (2012) Niche-associated activation of rac promotes the asymmetric division of Drosophila female germline stem cells. PLoS Biol 10:e1001357