Cells within many tissues and organs are continually replenished throughout our lives. This is accomplished by stem cells, which balance self-renewal with more differentiated cell types. The mechanisms that control this balance are not clear. In tissues maintained by stem cells, the differentiating daughters undergo mitotic expansion before generating tissue-specific cell types. The mechanisms that control transit amplification are also not clear. Both of these phenomena are featured in Drosophila spermatogenesis, where stem cell daughters choose between self-renewal and differentiation, and where transit amplifying gonial cells switch to spermatocyte development. Gonial cells divide four times; the counting and effector mechanisms regulating this are unknown.
Aim 1 tests the hypothesis that germ cells count intrinsically, and then collaborate with surrounding somatic cells to coordinate the spermatocyte transition. We discovered that a somatic cell signal promotes differentiation of stem cell daughters, while other labs discovered a signal that promotes self-renewal.
Aim 2 tests the hypothesis that self-renewal and differentiation are indeed balanced by these competing signals, and then investigate how they compete. To generate and begin to test biologically based hypotheses for other candidate factors and signaling pathways that legislate between renewal and differentiation we have conducted transcript-profiling analyses of self-renewing cells or their differentiating daughters.
Aim 3 proposes to complete these studies and conduct functional tests on selected candidates.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM060804-05
Application #
6685040
Study Section
Reproductive Biology Study Section (REB)
Program Officer
Greenberg, Judith H
Project Start
1999-08-01
Project End
2007-07-31
Budget Start
2003-08-01
Budget End
2004-07-31
Support Year
5
Fiscal Year
2003
Total Cost
$306,670
Indirect Cost
Name
University of Pennsylvania
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Ly, Dan; Resch, Erin; Ordiway, George et al. (2017) Asymmetrically deployed actomyosin-based contractility generates a boundary between developing leg segments in Drosophila. Dev Biol 429:165-176
Wingert, Lindsey; DiNardo, Stephen (2015) Traffic jam functions in a branched pathway from Notch activation to niche cell fate. Development 142:2268-77
Lenhart, Kari F; DiNardo, Stephen (2015) Somatic cell encystment promotes abscission in germline stem cells following a regulated block in cytokinesis. Dev Cell 34:192-205
Dinardo, Stephen; Okegbe, Tishina; Wingert, Lindsey et al. (2011) lines and bowl affect the specification of cyst stem cells and niche cells in the Drosophila testis. Development 138:1687-96
Okegbe, Tishina C; DiNardo, Stephen (2011) The endoderm specifies the mesodermal niche for the germline in Drosophila via Delta-Notch signaling. Development 138:1259-67
Zheng, Qi; Wang, Yiwen; Vargas, Eric et al. (2011) magu is required for germline stem cell self-renewal through BMP signaling in the Drosophila testis. Dev Biol 357:202-10
Leatherman, Judith L; Dinardo, Stephen (2010) Germline self-renewal requires cyst stem cells and stat regulates niche adhesion in Drosophila testes. Nat Cell Biol 12:806-11
Leatherman, Judith L; Dinardo, Stephen (2008) Zfh-1 controls somatic stem cell self-renewal in the Drosophila testis and nonautonomously influences germline stem cell self-renewal. Cell Stem Cell 3:44-54
Franklin-Dumont, Tina M; Chatterjee, Chandrima; Wasserman, Steven A et al. (2007) A novel eIF4G homolog, Off-schedule, couples translational control to meiosis and differentiation in Drosophila spermatocytes. Development 134:2851-61
Wallenfang, Matthew R; Nayak, Renuka; DiNardo, Stephen (2006) Dynamics of the male germline stem cell population during aging of Drosophila melanogaster. Aging Cell 5:297-304

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