Erika Bach, PhD

Erika BachAssociate Professor of Biochemistry and Molecular Pharmacology
Ph.D., 1996, Washington University
Post Doc, 1997-2002, Harvard Medical School

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
E-mail: erika.bach@nyu.edu

Lab Website: http://bachlab.med.nyu.edu/
Research Theme(s): Eye Development, Segmentation and Pattern Formation, Signal Transduction, Stem Cell Biology
Keywords: JAK/STAT, Chinmo, Germ-line Stem Cell, Somatic Stem Cell, Self-renewal, Cell Competition

Research Summary:

Roles of JAK/STAT pathway in growth and stem cell self-renewal in Drosophila 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 recently shown that chinmo is a gene that is cell-autonomously and positively regulated by JAK/STAT signaling (Flaherty et al, Dev Cell 2010).  We have also shown that Chinmo, like activated Stat92E, is expressed in both germ-line stem cells (GSCs) – where Stat29E is required for adhesion of the GSC to the niche) and CySCs in the testis.  Like Stat92E, we find that 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 in CySCs can support GSCS non-autonomously outside of the niche.  We find that sustained mis-expression of chinmo in CySCs also support GSCs away from the niche.  We are interested in determining the degree to which Chinmo can substitute for Stat92E in CySCs (and vice versa).  We are also investigating whether chinmo is essential for the maintenance of other stem cell populations that require JAK/STAT pathway activity for self-renewal.

Cellular Function of Chinmo in Stem Cells

We recently showed that chinmo is a cell-autonomous, downstream mediator of the JAK/STAT pathway that shares numerous functions with this protein (Flaherty et al, Dev Cell 2010).  Loss of either Stat92E or chinmo results in malformed eyes and head capsules due to defects in eye progenitor cells.  Furthermore, hyperactivation of Stat92E or misexpression of Chinmo results in blood cell tumors.  Chinmo is protein 604 amino acid protein with one N-terminal BTB domain and two C2H2 Zinc fingers of unknown cellular function.  Chinmo might repress gene transcription by binding histone deacetylases (HDACs) or promote protein degradation by interaction with Cullin3 E3 ligases.  The targets of Chinmo may represent important factors in stem cell self-renewal, growth control and development.  We are currently performing ChIP-on-chip experiments to determine which sites in the genome might be occupied by Chinmo.  We are also pursuing enzymatic ubiquitin substrate trap assays followed by mass-spectrometry to identify substrates of a putative Cul3-Chinmo complex.

Growth Control in Stem/Progenitor Cells

Tissue size during development is controlled by three processes: proliferation, cellular size (also called mass accumulation or cellular growth) and cell death. Over-expression of the ligand Unpaired (Upd) leads to enlarged adult eyes and a dramatic increase in stem cell numbers in the testis. By contrast, reducing Stat92E function has the opposite phenotype (Bach et al, Genetics 2003). We have shown that cells responding to the ectopic Upd show additional rounds of mitosis as well as increased cellular growth. We and others have shown that activated Stat92E does not seem to have a role per se in protecting cells from apoptosis. However, the molecular mechanisms used by the JAK/STAT pathway to promote proliferation and mass accumulation are not yet known. To identify them, we are using well-established genetic assays and flow cytometry on cells in the wing disc.

Cell Competition

Cell competition is a conserved mechanism that regulates tissue size and shares properties with tissue regeneration and the early stages of cancer.  In Drosophila, wing progenitor cells with increased Myc or with optimal ribosomal function become supercompetitors that kill their wild type neighbors (called losers) up to several cell diameters away.  However, only Myc and its activator Yorkie/YAP have been shown to confer supercompetitor status.  We recently determined that wing cells with hyper-activation of the JAK/STAT pathway become supercompetitors that kill losers located at a distance and in a Myc-independent manner.  Remarkably, we find that hyper-activating STAT in null-Myc cells rescues them competitive stress without increasing ribosome biogenesis or activation of Yorkie. These results indicate that Stat92E and dMyc are major parallel regulators of cell competition that may ultimately converge on a signal that non-autonomously kills losers. Since hyper-activated STATs are causal to tumorigenesis and niche occupancy of stem cells, our results have therapeutic implications for cancer and regenerative medicine. These results are currently under review (Rodrigues et al, in revision).  In future studies, we will determine how activated Stat92E regulates cell competition by micro-array approaches on FACS-sorted winners with hyper-activated Stat92E.

Pattern Formation

Imaginal discs are comprised of epithelial progenitor cells, which grow in the larva, evert in the pupa and become functional in the adults.  We previously showed that JAK/STAT pathway activity is required for the formation of the eye field during larval development (Ekas et al. Development 2006).  This occurs, at least in part, by the repression of the wingless and Serrate genes by activated Stat92E (Ekas et al. Development 2006; Flaherty et al, Dev Dyn 2009).  We also reported that the JAK/STAT pathway plays an essential role in the formation of the proximo-distal axis in the antenna and the leg.  This occurs in part through Stat92E-mediated repression of wg and dpp genes, as well as Wg- and BMP-pathway dependent repression of the upd gene (Ayala-Camargo 2007 Dev Dyn).  In the eye, antenna and leg discs, we believe that Stat92E mediates its effect through additional, as-yet unidentified genes that we are interested in identifying.  We now are studying the role of the JAK/STAT pathway in proximo-distal axis formation in the developing wing.  We find that Stat92E activity is initially broad in the wing disc but becomes refined to hinge as larval development proceeds.  Loss of Stat92E leads to loss of the adult wing hinge.  We are currently investigating the interaction between Stat92E, Teashirt and Nubbin. 

Selected Publications: