Erika Bach, PhD
Associate Professor of Biochemistry and Molecular Pharmacology
Ph.D., 1996, Washington University
Post Doc, 1997-2002, Harvard Medical School
Signal Transduction, Stem Cell Biology, stem cell differentiation
Self-Renewal, JAK/STAT, Chinmo, Germ-line Stem Cell, Somatic Stem Cell, Niche Competition, Hh, Hippo
New York University School of Medicine
Dept. of Pharmacology, MSB 497B
550 First Ave. New York, NY 10016
Tel: (212) 263-5963
Lab: (212) 263-7787
Fax: (212) 263-7133
Stem Cell Self-renewal
The JAK/STAT pathway is required for the self-renewal of multiple stem cell populations in Drosophila, including a somatic population called cyst stem cells (CySCs) in the testis. We have shown that chinmo is a gene that is cell-autonomously and positively regulated by JAK/STAT signaling (Flaherty et al, Dev Cell 2010). We reported that Chinmo, like activated Stat92E, is expressed in both germ-line stem cells (GSCs) – where Stat92E is required for adhesion of the GSC to the niche) and CySCs in the testis. Like Stat92E, chinmo is required for the self-renewal of CySCs. Also like Stat92E, chinmo is not required for the maintenance of GSCs. Sustained activation of Stat92E (or mis-expression of Chinmo) in CySCs can support GSCS non-autonomously outside of the niche.
We are investigating the requirement for additional factors in self-renewal of testis stem cells. It is known that niche cells produce Hedgehog (Hh), but the role of Hh in this tissue was not elucidated until recently. We used clonal analysis to show that Hh signal transduction is specifically required only in CySCs (and not in GSCs) for their self-renewal (Amoyel et al, Development 2013). Genetic epistasis experiments show that Hh functions in parallel to STAT and MAPK in CySC self-renewal. However, unlike STAT, Hh signaling does not contribute to the extended niche function of CySCs.
The ability of an individual stem cell to contribute to tissue homeostasis over the life of an organism depends on its continued residency at its niche. Neutral competition, an emerging feature of stem cell homeostasis, posits that individual stem cells can be lost and replaced by their neighbors stochastically, resulting in chance dominance of a clone at the niche. A single stem cell with an oncogenic mutation could bias this neutral process of stem cell replacement in its favor and clonally spread the mutation throughout the stem cell pool; however. The Drosophila testis provides an ideal system for testing this model. The niche supports two stem cell populations, GSCs and CySCs, which compete for niche occupancy. We find that CySCs conform to the paradigm of neutral competition and that clonal deregulation of either the Hh or Hippo (Hpo) pathway or simply clonally accelerating proliferation allows a single CySC to colonize the niche and displace GSCs. We find unexpectedly no causal role for JAK/STAT signaling or adhesion in colonization. Rather, the driving force behind such behavior is accelerated proliferation. Instead clonally accelerating the cell cycle in CySCs causes them to outcompete wild-type CySCs and GSCs. Finally, clonal inactivation of the Hippo pathway in CySCs also causes them to outcompete wild-type neighboring stem cells. These results demonstrate that a single stem cell colonizes its niche through oncogenic mutation by co-opting an underlying homeostatic process and not by acquiring a neomorphic function (Amoyel et al., in revision).
Molecular targets of Chinmo in stem cells
The molecular function of Chinmo is not known, but it has one Bric-à-brac Tramtrack Broad (BTB) and two Zinc finger (ZF) domains, which are required for function. BTB and ZF domain proteins can repress transcription in a site-specific manner by recruiting HDACs or co-repressors. Consistent with this, we found that Serrate is ectopically expressed in chinmo clones, suggesting that Chinmo can act as a transcriptional repressor. To find potential targets for Chinmo in CySCs, we are FACS purifying CySCs from wild-type, chinmo-over-expressing and chinmo-knockdown animals and then performing micro-arrays. Furthermore, our collaborators Drs. Scot Wolfe and Michael Brodsky (UMassMed, Worcester, MA, USA) – both experts on ZF proteins – are using the bacterial one-hybrid (B1H) technology to determine a potential DNA binding specificity for Chinmo, which should be present in genes by micro-array.
Germline stem cell aging
Aging is a process fundamental to all organisms and is related to many human diseases such as cancer and dementia. Some aspects of aging are due to acquired defects in the adult stem cells that maintain the function of many organs. In contrast to these somatic stem cells, germline stem cells (GSCs) are supposed to be immortal as their lineage is perpetuated through the next generation. This project aims to unravel the causes and effects of aging on testis stem cells by studying these two populations. The results from this study are likely to impact regenerative biology as well certain stem cell pathologies like cancer. Our analysis includes characterizing the relevance of the de-differentiation phenomenon in the maintenance of the GSC population; determining the role of non-autonomous factors in the aging of CySCs, GSCs and their niche; assessing which cells (stem, niche or other tissues) require proteasome and anti-oxidative activities for preventing the aging of stem cells.
- M. Amoyel, B. D. Simons & E. A. Bach, Neutral competition of stem cells is skewed by proliferative changes downstream of Hh and Hpo, in revision at EMBO J. PMID: 25092766
- M. Amoyel and E. A. Bach (2014) Cell competition: how to eliminate your neighbours Development. 141(5):988-1000. PMID: 24550108
- A. Ayala-Camargo, A. M. Anderson, M. Amoyel, A. B. Rodrigues, M. S. Flaherty & E. A. Bach (2013). JAK/STAT signaling is required for hinge growth and patterning in the Drosophila wing disc. Developmental Biology Oct 15;382(2):413-26. PMID: 23978534
- H. Court, M. Amoyel, M. Hackman, K. E. Lee, R. Xu, G. Miller, D. Bar-Sagi, E. Bach, M. Bergö and M. Philips (2013). lcmt Deficiency Exacerbates a K-Ras-driven Mouse Model of Pancreatic Neoplasia by Suppressing Notch Signaling. Journal of Clinical Investigation 123(11):4681-94. PMID: 24216479
- M. Amoyel, J. Sanny, M. Burel & E. A. Bach. (2013) Hedgehog is required for CySC self-renewal but does not contribute to the GSC niche in the Drosophila testis. Development 140: 56-65. PMID: 23175633
- A.B. Rodrigues, A. Ayala-Camargo, S. Grewal, T. Reyes-Robles, M. Krasny, D.C. Wu, L.A. Johnston & E. A. Bach. (2012) Activated STAT regulates growth and induces competitive interactions independently of Myc, Yorkie, Wingless and ribosome biogenesis. Development. 139: 4051-4061. PMID: 22992954
- P. J. Sung, A. Rodrigues, A. Kleinberger, S. Quatela, E. A. Bach* & M. R. Philips* (2010). Cytosolic Ras Supports Eye Development in Drosophila. Molecular and Cellular Biology. 30(24):5649-57. *co-corresponding authors [and cover image]. PMID: 20937772
- L. A. Ekas, T. J. Cardozo, M.S. Flaherty, E. McMillan, F. Gonsalves & E. A. Bach, (2010) Characterization of a dominant-active STAT that promotes tumorigenesis in Drosophila, Developmental Biology, Aug 15;344(2):621-36. PMID: 20501334
- M.S. Flaherty, P. Salis, C. J. Evans, L. A. Ekas, A. Marouf, J. Zavadil, U. Banerjee & E. A. Bach (2010). chinmo is a functional effector of the JAK/STAT pathway that regulates eye development, tumor formation and stem cell self-renewal in Drosophila. Developmental Cell 18(4): 556-568. PMID: 20412771