Stavroula Mili, Ph.D.
Dr. Mili discovered a localization pathway that targets RNAs at cellular protrusions. RNAs targeted through this pathway depend for their localization on the APC tumor-suppressor and are deregulated by pathologic RNA granules associated with neurodegeneration. The goal of her lab is to understand the regulation, functional consequences and disease associations of localized RNAs.
Regulation and Functions of Localized RNAs
It is becoming increasingly appreciated that, virtually in all polarized mammalian cells, a large number of mRNAs do not exist diffusely in the cytoplasm, but undergo specific subcellular targeting and local control of their translation. Such localized RNAs are important for various processes such as migration, epithelial cell polarity, mitotic spindle assembly and neuronal function. Defects in RNA localization are implicated in diseases such as mental retardation and cancer metastasis. Our lab aims to understand the mechanisms and regulation of RNA localization in mammalian cells, the effect of localized translation on protein function, and the contribution of these processes to disease.
A. The APC-dependent RNA localization pathway. We have identified an RNA localization pathway that targets numerous mRNAs to cellular protrusions (Mili et al, Nature 2008). A central component of this pathway is the tumor suppressor protein adenomatous polyposis coli (APC), which is disrupted in most colorectal cancers. APC is required for localization of RNAs at protrusions, suggesting that their deregulation might contribute to tumor progression (Trends Cell Biol. 2009). Interestingly, localization of APC-dependent RNAs is important for cell migration and is regulated by the stiffness of the extracellular environment. The underlying mechanism involves mechanosensitive signaling pathways and a subset of post-translationally modified, detyrosinated microtubules, providing the first link between modified microtubules and RNA transport events (Wang et al, Nature Commun. 2017). We aim to understand the functions fulfilled by APC-dependent RNAs, their regulation by the mechanical properties of the extracellular environment and the contribution of their disruption to cancer progression.
B. Deregulation of localized RNAs by pathological RNA inclusions. Another component of APC-RNPs is the RNA-binding protein FUS. Wild-type FUS associates with RNAs at protrusions and likely regulates their translation (Yasuda et al., J. Cell Biol. 2013). FUS belongs to a group of proteins with low-complexity, prion-like domains, which drive formation of membrane-less inclusions/granules, through a process of liquid-liquid phase separation. Inclusion formation by FUS is enhanced by the presence of mutations associated with ALS (amyotrophic lateral sclerosis). We found that cytoplasmic inclusions formed by ALS-FUS mutants preferentially recruit APC-RNPs. Interestingly, APC-RNPs are not silenced within FUS inclusions, but are being actively translated (Yasuda et al., J. Cell Biol. 2013). Formation of FUS inclusions additionally disrupts APC-RNP localization by sequestering the kinesin-1 motor protein and inhibiting formation of detyrosinated microtubules (Yasuda et al., J. Cell Biol. 2017). We are interested in understanding the interplay between RNA granule formation and RNA translation and the functional consequences of physiologic or pathologic RNA granule formation.
We are using a variety of microscopy-based approaches, quantitative image analysis, single-molecule RNA imaging, biochemical assays and high-throughput sequencing.
Selected Recent Publications
Extracellular matrix stiffness and cell contractility control RNA localization to promote cell migration.Nature Communications. 2017. [ Journal Article ]
FUS inclusions disrupt RNA localization by sequestering kinesin-1 and inhibiting microtubule detyrosination.J.Cell Biol.. 216: 1015-1034, 2017. [ Journal Article ]
- Wiley Interdiscip Rev RNA . 7: 589-603, 2016. [ Journal Article ]
- J. Cell Biol. 203: 737-46, 2013. [ Journal Article ]
- Nature. 453: 115-9, 2008. [ Journal Article ]
Stavroula (Voula) Mili obtained her BSc degree in Biology from the University of Athens, Greece and her PhD degree in Biomedical Sciences from the Mount Sinai School of Medicine of New York University under Dr. Serafin Pinol-Roma. For her post-doctoral training she joined Dr. Joan Steitz's lab at Yale University and subsequently Dr. Ian Macara's lab at the University of Virginia. She joined the Laboratory of Cellular and Molecular Biology at the NCI in September 2012.
|George Chrisafis||Postbaccalaureate Fellow|
|Michael Stueland||Postbaccalaureate Fellow (CRTA)|
|Tianhong Wang Ph.D.||Research Biologist|
|Kyota Yasuda Ph.D.||Postdoctoral Fellow (Visiting)|