Krill Prize 2014
Dr. Lilach Gilboa (ד”ר לילך גלבוע)
Stem Cell and Developmental Biology
Adult stem cells support regeneration of many tissues in resting conditions and following injury. This ability is tightly connected to cues these cells receive from their environment (niche). Understanding how stem cell units (stem cells within their niches) form and how they function is imperative to our understanding of organismal biology and for rational design of strategies for regenerative interventions. Our lab uses the ovary of Drosophila melanogaster as a model to find novel genes and biological principles that underlie the formation and function of germ line stem cells (GSCs). Our findings bear direct implications to mammalian regeneration and adult stem cell function, respectively. We are particularly interested in co-regulation of niche formation with GSC establishment and in physiological inputs into the process of organogenesis. Our work thus far suggests two important biological principles: First: the development of niche and GSC precursors is co-regulated such that the numerical ratios and the timing of differentiation of each cell type can be adjusted to make the appropriate stem cell unit numbers. Second, that stem cell unit formation involves not only local signals, but is orchestrated by hormones. This allows gonadogenesis to be coordinated with other developing organs and with external conditions.
1. Hormonal regulation of gonadoenesis. We discovered that receptors for the hormone ecdysone act as a switch between proliferation and differentiation of both niche and GSC precursors. This finding (published in PLoS Biology) exemplified for the first time co-formation of niches and stem cells. It provided a framework for understanding not only lineage differentiation within the ovary, but how it is united with proliferation. It therefore provides a chance to understand size control in organs that contain more than one cell type as well as stem cell unit formation. The major target of ecdysone in the ovary is the transcription factor Broad. Current work in the lab concentrates on additional regulators of Broad expression, and on its target genes, which direct stem cell unit differentiation. Two additional papers that will be submitted shortly provide deeper understanding of coordinated stem cell unit formation. The first (Lengil et al., in-prep) shows that following activation of the broad locus by ecdysone, the rate of Broad accumulation depends on Activin signaling. Activin also controls proliferation independently of ecdysone, thus providing another integration point for differentiation and proliferation. The second paper (Hitrik et al., in-prep) introduces the transcription factor Combgap as a selector between different broad isoforms and provides data showing it acts as a tethering protein between promoters and enhancers.
2. Nutritional regulation of germ cell biology. We have recently shown that nutritional input via Tor and InR signaling also serves to coordinate stem cell unit formation (Development, 2013). One major finding that arises from this study is that InR (but not Tor) signaling non-autonomously controls germ cell differentiation. Thus, nutritional cues can integrate on the major axis of GSC maintenance and differentiation. While performing experiments for this study we discovered a trans-generational effect of starvation on gonad formation. We are now studying the epigenetic mechanisms that underlie this effect.
3. Soma-germ line interactions and GSC differentiation. We recently submitted a paper (Maimon et al., Submitted) showing that Stat signaling, which is a known GSC maintenance signal, is also required to differentiate them. This is a first instance where the same signal is shown to serve such opposite ends. Molecularly, we show that the chromatin binding-protein Without Children (Woc) cooperates with Stat to up-regulate Zfh-1, which, in turn, allows somatic cells to contact germ cells. The Stat-Woc-Zfh-1 module is required for soma-germ line interactions throughout the animal’s life time, explaining the seemingly opposite requirement for Stat in GSC maintenance (attachment to the niche) and differentiation (attachment to support cells controlling differentiation). In a continuation of this study we examine the role of Stat and MAPK signaling in promoting motility in somatic support cells. Both pathways are continually active in these cells, mimicking certain motile metastases that also depend on constant activation of Stat and MAPK in order to spread.
4. Finding novel genes that control GSC biology. The lab has undertaken two types of screens. In collaboration with Trudy Mackay, at the North Carolina State University, we initiated a genome-wide association study of naturally variating fly lines in order to find novel quantitative trait loci that affect niche formation. Based on previous experience, we expect to find many novel genes by this genetic approach. In addition, we are systemically mutating germ cell specific cell surface molecules in order to find how germ cells perceive somatic cues that direct them to proliferate, be maintained or differentiate.