The molecular mechanisms controlling stem cell self-renewal versus differentiation hold great potential for advances in cancer biology, aging and regenerative medicine. Increasing the pool of stem cells provides a condition for oncogenesis;tumors have """"""""cancer stem cells"""""""" that self-renew and establish metastases. A critical regulator of stem cell numbers in mammals is the JAK/STAT pathway. Inappropriate activation of mammalian JAKs and STATs cause cancer and inhibiting their activity blocks the growth of primary human cancer cells. These data suggests that developing drugs which specifically inhibit JAKs or STATs, could offer novel treatments for cancer patients. Despite these compelling observations, the mechanisms utilized by this pathway to regulate stem cell numbers in mammals have not yet been elucidated. Mammals have multiple jak and stat genes, making the analysis of their in vivo function difficult. Drosophila offers an ideal system to address this issue, as its control of stem cell numbers is conserved in several tissues, including the testis and eye. Drosophila has only one jak and one stat (called stat92E) and offers facile in vivo analysis. This application concerns the dissection of molecular mechanisms used by the JAK/STAT pathway to regulate stem cell number in Drosophila. Three distinct processes must occur in a coordinated manner for stem cell populations to be maintained: increase in cellular mass, mitosis and self-renewal. Since Stat92E is a transcription factor, discrete Stat92E target genes should mediate its effects on these processes. Three such genes with human homologs, cyclin E (cycE), dmyc and chinmo, appear to reside directly downstream of Stat92E. CycE is the rate-limiting regulator of the cell cycle and its expression is increased by Stat92E in a cell- autonomous manner. dMyc is the sole c-Myc family member in Drosophila and is a critical regulator of cellular growth. Stat92E increases protein synthesis and may act through dMyc to do so. chinmo encodes a novel nuclear protein and is regulated by Stat92E in a cell-autonomous manner. Like Stat92E, Chinmo is required within testis stem cells for their self-renewal. The identification of Stat92E-regulated targets with links to mitosis, cellular growth and self-renewal is a major advance in our understanding of the growth-regulatory properties of the JAK/STAT pathway.
Aim 1 (Characterize the effects of JAK/STAT signaling on proliferation) employs molecular methods and FACS analysis to measure the effects of JAK/STAT signaling on proliferation rates, cell cycle phasing and expression of critical cell cycle factors.
Aim 2 (Determine if Stat92E regulates cellular growth through dMyc) uses genetic approaches and FACS analysis to measure the effects of Stat92E on cellular growth and to determine if it regulates this process through dmyc.
Aim 3 (Determine if Stat92E regulates self-renewal in through chinmo) uses genetic and molecular approaches to determine if Stat92E regulates self-renewal in testis stem cells through chinmo alone or through additional target genes.

Public Health Relevance

Due to evolution, JAK and STAT genes exist in very similar forms in other organisms, such as the fruit fly Drosophila. The fruit fly is an excellent genetic organism that has been used for many years in research laboratories and with great success to identify and characterize genes critical for basic biological processes. Our study is designed to eludicate how the JAK/STAT pathway regulates stem cell numbers in Drosophila.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM085075-03
Application #
8019998
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Maas, Stefan
Project Start
2009-02-01
Project End
2014-01-31
Budget Start
2011-02-01
Budget End
2012-01-31
Support Year
3
Fiscal Year
2011
Total Cost
$307,335
Indirect Cost
Name
New York University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Cook, Matthew S; Cazin, Coralie; Amoyel, Marc et al. (2017) Neutral Competition for Drosophila Follicle and Cyst Stem Cell Niches Requires Vesicle Trafficking Genes. Genetics 206:1417-1428
Court, Helen; Ahearn, Ian M; Amoyel, Marc et al. (2017) Regulation of NOTCH signaling by RAB7 and RAB8 requires carboxyl methylation by ICMT. J Cell Biol 216:4165-4182
Anderson, Abigail M; Bailetti, Alessandro A; Rodkin, Elizabeth et al. (2017) A Genetic Screen Reveals an Unexpected Role for Yorkie Signaling in JAK/STAT-Dependent Hematopoietic Malignancies in Drosophila melanogaster. G3 (Bethesda) 7:2427-2438
Amoyel, Marc; Hillion, Kenzo-Hugo; Margolis, Shally R et al. (2016) Somatic stem cell differentiation is regulated by PI3K/Tor signaling in response to local cues. Development 143:3914-3925
Amoyel, Marc; Anderson, Jason; Suisse, Annabelle et al. (2016) Socs36E Controls Niche Competition by Repressing MAPK Signaling in the Drosophila Testis. PLoS Genet 12:e1005815
Amoyel, Marc; Bach, Erika A (2015) MT-Nanotubes: Lifelines for Stem Cells. Cell Stem Cell 17:133-4
Amoyel, Marc; Anderson, Abigail M; Bach, Erika A (2014) JAK/STAT pathway dysregulation in tumors: a Drosophila perspective. Semin Cell Dev Biol 28:96-103
Amoyel, Marc; Simons, Benjamin D; Bach, Erika A (2014) Neutral competition of stem cells is skewed by proliferative changes downstream of Hh and Hpo. EMBO J 33:2295-313
Amoyel, Marc; Bach, Erika A (2014) Cell competition: how to eliminate your neighbours. Development 141:988-1000
Amoyel, Marc; Sanny, Justina; Burel, Michael et al. (2013) Hedgehog is required for CySC self-renewal but does not contribute to the GSC niche in the Drosophila testis. Development 140:56-65

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