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Ian
G.
Macara
Degree(s): Ph.D. Graduate School: University of Sheffield, United Kingdom Primary Appointment: Professor of Microbiology Research Interests: Mammary Gland Morphogenesis, Stem Cells, and Breast Cancer; Mechanisms of Cell Polarity; Polarity Proteins as Tumor Suppressors; Protein Methylation. Email Address: igm9c@virginia.edu |
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Biomedical Sciences Graduate Program(s) Research Description Mammary Morphogenesis and Breast Cancer. The mammary gland is an ideal tissue in which to study the function of stem cells, interactions betwee.n different cell types, and the development of structures such as branched tubules. Defects in ductal development can result in breast cancer. Since there are several hundred thousand new cases of breast cancer a year, in the US alone, these studies also have major clinical importance. To study mammary morphogenesis we have developed new technologies in which we isolate mammary stem cells from mice, transduce the stem cells with lentivirus to manipulate gene expression in them, and then transplant the transduced cells into the cleared fat pads of host mice. An entire new mammary gland regenerates from the implanted stem cells. By studying the effects of gene silencing (using RNA interference) we can quickly determine the function of the gene in morphogenesis. Moreover, we can easily do knock-ins by incorporating a mutant cDNA into the lentivirus along with the shRNA to silence the endogenous gene. In an extension of this powerful technology, we can grow mouse or human mammary tissue in explant cultures under conditions in which they recapitulate normal ductal morphogenesis. We can image these organoid cultures in real time, using a spinning disk microscope, and ask how ducts and branches form, and what function specific genes have in these processes. We are interested in recruiting new graduate students and postdocs to extend and employ these exciting new technologies to address major questions in morphogenesis and cancer initiation and metastasis. Molecular Mechanisms of Cell Polarization. We are using 3D cultures of epithelial cells, and dissociated hippocampal neuron cultures to determine the molecular function of polarity proteins in the establishment of apical/basal polarity and dendritic spine morphogenesis (Chen and Macara, Nature Cell Biol. 2005; Zhang and Macara, Dev. Cell 2008). We are using live cell imaging to try and understand the earliest events in the initiation of cell polarity. In addition, we have performed the first genome-wide screen for localized mRNAs in mammalian cells, and discovered a novel mechanism that anchors a subset of mRNAs to the plus ends of stable microtubules. This mechanism involves a tumor suppressor called APC (Mili et al., Nature 2008). We have recently been awarded a Human Frontier Science Program grant to work with scientists in Switzerland and New Zealand on the identification of zip codes that localize these RNAs to microtubule tips. We are seeking new students and postdocs to participate in this program, to understand how polarity proteins contribute to epithelial and neuronal polarity, and to study the molecular basis for the epithelial/mesenchymal transitions that are important in cancer cell dissemination. Protein Methylation. While studying a chromatin protein called RCC1, we discovered a very unusual form of post-translational modification, called a-N-methylation. The N-terminal methionine residue of RCC1 is cut off, and the exposed Serine (or Proline in some species) is methylated on its alpha amino group. Remarkably, this modification alters the affinity of the RCC1 for chromatin, and can prevent chromosomal mis-segregation during mitosis (Chen et al, Nature Cell Biol, 2007). We have now discovered the novel methyltransferase responsible for this modification, and found dozens of additional targets, some of which have functions in cell cycle control. We are looking for new students and postdocs with an interest in pursuing these novel targets, to determine the functions of the methylation. |