Daniela Drummond-Barbosa, Ph.D. Department of Biochemistry and Molecular Biology

Transcription

1 Control of stem cells by diet and systemic factors in the Drosophila ovary Daniela Drummond-Barbosa, Ph.D. Department of Biochemistry and Molecular Biology

2 Multiple levels of stem cell regulation local signals niche cellintrinsic factors stem cell unequal daughter cell diet aging stress infection injury disease differentiating progeny systemic factors

3 Stem cells respond to aging-related physiological changes Snoeck (2005) Nature Biotechnology 23, (News&Views) Conboy et al. (2005) Science 443,

4 Dietary/systemic influences on stem cells?

5 Multiple levels of stem cell regulation local signals niche cellintrinsic factors stem cell unequal daughter cell differentiating progeny systemic factors How do stem cells respond to the external and physiological environments?

6 Stem cells in the Drosophila ovary Drosophila ovary

7 The Drosophila ovary responds to diet follicle stem cells follicle cells Eggs / female / day Rich Poor INSULIN SIGNALING REQUIRED Time (days) follicle cell germline cyst Germline division and development rates: Follicle cell division rates: Rich Poor Rich Poor Time (days) Drummond-Barbosa & Spradling (2001) Dev. Biol. 231,

8 Insulin signals control GSC proliferation DIRECTLY via PI3K/FoxO at G2, but additional signals are involved Insulin-like peptides Niche GSC LaFever and Drummond-Barbosa (2005) Science 309, Hsu, LaFever and Drummond-Barbosa (2008) Dev. Biol. 313,

9 Do diet and insulin-like peptides control germline stem cell? Diet/DILPs Diet/DILPs GSC??? Cell division cycle Hwei-Jan Hsu Niche GSC *GSCs lost at higher rates on a poor diet or under low insulin signaling (not direct effect) Hsu and Drummond-Barbosa (2009) Proc. Natl Acad. Sci. USA 106,

10 Insulin signaling controls the number of s *dinr expression in somatic cells rescues GSC and loss Hsu and Drummond-Barbosa (2009) Proc. Natl Acad. Sci. USA 106,

11 controls numbers Do insulin signals control activation in the niche? wild type pathway overactivation Song et al. (2007) Development 134: Ward et al. (2006) Current Biology 16:

12 Insulin signaling controls activation in the niche *genetic interaction between N and dinr *activated N rescues dinr ( and GSC loss) dinr mutant β-gal: hh-lacz expression in s and terminal filament CD2: E(spl)mβCD2, a transcriptional reporter of activation Hsu and Drummond-Barbosa (2009) Proc. Natl Acad. Sci. USA 106,

13 How do insulin signals control N activation in the niche? ILPs? ILPs? Sending of N signals? Responding to N signals?

14 Insulin signaling cell autonomously controls the competence of s to respond to ligands Hsu and Drummond-Barbosa (2011) Dev. Biol. 350,

15 Diet Age Insulin receptor Insulin-like peptides Insulin receptor PI3K PI3K FOXO Delta Insulin receptor PI3K FOXO formation FOXO Delta Delta GSC GSC proliferation GSC *But also effect on -GSC attachment LaFever and Drummond-Barbosa (2005) Science 309, Hsu and Drummond-Barbosa (2009) Proc. Natl Acad. Sci. USA 106, Hsu and Drummond-Barbosa (2011) Dev. Biol. 350,

16 Insulin influences E-cadherin at the GSC- junction *N mutation does not affect GSC- attachment or E-cadherin levels [Hsu and Drummond-Barbosa, (2011) Dev. Biol. 350, ] Hsu and Drummond-Barbosa (2009) Proc. Natl Acad. Sci. USA 106,

17 Diet Age Insulin receptor Insulin-like peptides Insulin receptor PI3K PI3K FOXO Delta Insulin receptor PI3K FOXO formation FOXO Delta E-cadherin Delta GSC GSC proliferation GSC LaFever and Drummond-Barbosa (2005) Science 309, Hsu and Drummond-Barbosa (2009) Proc. Natl Acad. Sci. USA 106, Hsu and Drummond-Barbosa (2011) Dev. Biol. 350,

18 Drosophila male GSCs and intestinal SCs

19 What other systemic signals mediate the response of GSCs to diet? Diet Age Insulin receptor Insulin-like peptides Delta Insulin receptor PI3K FOXO formation Insulin receptor PI3K FOXO Delta E-cadherin Delta GSC PI3K FOXO GSC proliferation GSC TOR Amino acids? LaFever, Feoktistov, Hsu & Drummond-Barbosa (2010). Development 137: ? Elizabeth Ables

20 Steroid signaling controls GSC (and proliferation) Ables and Drummond-Barbosa (2010) Cell Stem Cell 7,

21 How does ecdysone control GSC division and? Xie T., Germline stem cell niches (September 30, 2008), StemBook, ed. The Stem Cell Research Community, StemBook, doi/ /stembook ,

22 Ecdysone controls BMP signaling in GSCs Ables and Drummond-Barbosa (2010) Cell Stem Cell 7,

23 Working model Positive feedback: Steroid hormone made by more differentiated stages under favorable conditions acts via chromatin remodeling factors to promote response of GSCs to niche signals Ables and Drummond-Barbosa (2010) Cell Stem Cell 7,