Featured Publications
How tumors break the system
Ngo, S.*, Liang, J.*, Su, Y.H., & O’Brien, L.E. (2020) Disruption of EGF feedback by intestinal tumors and neighboring cells in Drosophila. Current Biology 30,1537-1546 | pdf | supplement *co-first authors
How do nascent tumors subvert normal feedback control of cell equilibrium? Early short-circuiting of feedback signaling in tumor-adjacent wild-type cells combines with later dysregulation in tumor cells to fuel chronic release of EGFs and activate feed-forward growth.
A see-through fly abdomen
Koyama, L.A.J., Aranda-Dias, A., Su, Y.H., Balachandra, S., Martin, J.L., Ludington, W.B., Huang, K.C., & O’Brien, L.E. (2020) Bellymount enables longitudinal, intravital imaging of abdominal organs and the gut microbiota in adult Drosophila. PLOS Biology 18:e3000567 | pdf | tutorial video
The adult fly abdomen is largely opaque to light, so researchers have traditionally studied abdominal organs by cutting flies open, which leads to their death. Bellymount is a simple, non-invasive imaging platform that creates a “see-through” abdomen to capture intravital, 3D snapshots of live, intact flies. We document the native spatial arrangement of internal organs and follow the longitudinal development of single midgut stem cell lineages and gut microbial colonization in the same animals over multiple days.
Unveiling the hidden lives of stem and differentiated cells
Martin, J.L., Sanders, E.N., Moreno-Roman, P., Koyama, L.A.J., Balachandra, S., Du, X., & O’Brien, L.E. (2018) Long-term live imaging of the Drosophila adult midgut reveals real-time dynamics of division, differentiation and loss. eLife 7:e36248 | pdf | tutorial video
“Windowmount” is the first methodology to visualize physiologically functioning midguts in live Drosophila adults, opening the door to the real-time study of organ renewal dynamics in vivo. Wide-field, micron-resolution imaging captures vivid movies over many hours to yield dynamic views of stem cell division, daughter cell differentiation, and terminal cell loss. New imaging analytics mitigate the effects of gut peristalsis and perform in toto spatial-temporal tracking of single cells. We show that mitotic stem cells dynamically re-orient, that daughter cells use slow kinetics of Notch activation to reach a fate-specifying threshold, and that enterocytes ex- trude via ratcheted constriction of a junctional ring.
Highlighted in: Drosophila Image Award, Runner-Up, Video category (2019) | Lewis, A. Freshen up: Detailed and direct observation of organ development. MRC Biomedical Picture of the Day (Jan 28, 2019) | Dye, N. A new method captures the dynamics of tissue homeostasis in the stem-cell based organ of the adult fly midgut. Company of Biologists preLights, Mar 20, 2018.
How organs balance cell division and death
Liang, J., Balachandra, S., Ngo, S., & O’Brien, L.E. (2017) Feedback regulation of steady-state epithelial turnover and organ size. Nature 548:588-591 | pdf | supplement
Steady-state organ turnover requires that cell addition and loss are held in precise equilibrium. Constitutive stem cell divisions were commonly thought to drive this process. To the contrary, we uncover a feedback mechanism in which the deaths of old, differentiated cells release a block on stem cell divisions. This mechanism serves to couple divisions to apoptosis, thereby targeting cell replacement to the appropriate time and place for zero-sum turnover.
Highlighted in: Principles of Systems Biology, No. 21. Liang, J. & O’Brien, L.E. (2017) Organ Size: Act Locally to Control Globally. Cell Systems 5:158-160 | Ferrarelli, L.K. (2017) A life-death relay in the gut. Science Signaling 10:495 | Dubnicoff, T. Stories that caught our eye last week: Dying cells trigger stem cells. The Stem Cellar (CIRM Blog), Sep 5, 2017 | Conger, K. “The Goldilocks Effect: Dying cells signal to keep organ size ‘just right’” Stanford Medicine Scope, Aug 31, 2017 | Faculty of 1000 F1000Prime.com/729075065
Prior key publications
O’Brien, L.E. & Bilder, D. (2013) Beyond the Niche: Tissue-level coordination of stem cell dynamics. Annu. Rev. Cell Dev. Biol. 29:107-136 | pdf
O’Brien, L.E., Soliman, S., Li, X., & Bilder, D. (2011) Altered modes of stem cell division drive adaptive intestinal growth. Cell 147:603-614 | pdf
O’Brien, L.E., Tang, K., Kats, E.S., Schutz-Geschwender, A., Lipschutz, J.H., & Mostov, K.E. (2004) ERK and MMPs sequentially regulate distinct stages of epithelial tubule development. Dev. Cell 7:21-32 | pdf
O’Brien, L.E., Zegers, M.M., & Mostov, K.E. (2002) Opinion: Building epithelial architecture: Insights from three-dimensional culture models. Nat. Rev. Mol. Cell Biol. 3:531-537 | pdf
O’Brien, L.E., Jou, T.S., Hansen, S.H., Pollack, A.L., Zhang, Q., Yurchenco, P.D. & Mostov, K.E. (2001) Rac1 orients epithelial apical polarity through effects on basolateral laminin assembly. Nature Cell Biol. 3:831-838 | pdf
All Publications
Kim, A.A., Nguyen, A., Marchetti, M., Du, X., Montell, D.J., Pruitt, B.L., O'Brien, L.E. (2022) Independently paced Ca2+ oscillations in progenitor and differentiated cells in an ex vivo epithelial organ. J Cell Sci (2022) 135 (14): jcs260249. PDF
Li, Hongjie, Jasper Janssens, Maxime De Waegeneer, Sai Saroja Kolluru, Kristofer Davie, Vincent Gardeux, Wouter Saelens et al. (2022) Fly Cell Atlas: A single-nucleus transcriptomic atlas of the adult fruit fly. Science 375, no. 6584: eabk2432. PDF
Ngo, S.*, Liang, J.*, Su, Y.H., & O’Brien, L.E. (2020) Disruption of EGF feedback by intestinal tumors and neighboring cells in Dro- sophila. Current Biology 30(8):1537-1546.e3. *co-first authors PDF
Koyama, L.A.J., Aranda-Dias, A., Su, Y.H., Balachandra, S., Martin, J.L., Ludington, W.B., Huang, K.C., & O’Brien, L.E. (2020) Belly- mount enables longitudinal, intravital imaging of abdominal organs and the gut microbiota in adult Drosophila. PLoS Biology 18(1):e3000567. PDF
Martin, J.L., Sanders, E.N., Moreno-Roman, P., Koyama, L.A.J., Balachandra, S., Du, X., & O’Brien, L.E. (2018) Long-term live imag- ing of the Drosophila adult midgut reveals real-time dynamics of division, differentiation and loss. eLife 7:e36248. PDF
Kim, A.A., Nekimken, A.L., Fechner, S., O’Brien, L.E., & Pruitt, B.L. (2018) Microfluidics for mechanobiology of model organisms. Methods in Cell Biology 146:217-259. PDF
Liang, J., & O’Brien, L.E. (2018) A gut feeling for cellular fate. Nature 555:34-36. PDF
Liang, J., Balachandra, S., Ngo, S., & O’Brien, L.E. (2017) Feedback regulation of steady-state epithelial turnover and organ size. PDF
Du, X., O’Brien, L.E.* & Riedel-Kruse, I.* (2017) A model for adult organ resizing demonstrates stem cell scaling through a tunable commitment rate. Biophys. J. 113:174-184. *co-corresponding authors PDF
O’Brien, L.E. & Bilder, D. (2013) Beyond the Niche: Tissue-level coordination of stem cell dynamics. Annu. Rev. Cell Dev. Biol. 29:107-136. PDF
O’Brien, L.E. (2013) Invited Preview - Regional specificity in the Drosophila midgut: setting boundaries with stem cells. Cell Stem Cell 13:375-376. PDF
O’Brien, L.E., Soliman, S., Li, X., & Bilder, D. (2011) Altered modes of stem cell division drive adaptive intestinal growth. Cell 147:603-614. PDF
Kim, M., O’Brien, L.E., Kwon, S.H., & Mostov, K.E. (2010) STAT1 is required for redifferentiation during Madin-Darby canine kidney tubulogenesis. Mol. Biol. Cell 21:3926-3933. PDF
O'Brien LE, Yu W, Tang K, Jou TS, Zegers M.M., Mostov K.E. (2006) Morphological and biochemical analysis of Rac1 in three-di- mensional epithelial cell cultures. Meth. Enzymol. 406:676-691. PDF
Yu, W., Datta, A., Leroy, P., O’Brien, L.E., Mak, G., Jou, T.S., Matlin, K.S., Mostov, K.E., & Zegers, M.M. (2005) β1-integrin orients epi- thelial polarity via Rac1 and laminin. Mol. Biol. Cell 16:433-445. PDF
Mostov, K.E., Brakeman, P., Datta, A., Gassama, A., Katz, L., Kim, M., Leroy, P., Levin, M., Liu, K., Martin, F., O’Brien, L.E., Verges, M., Su, T., Tang, K., Tanimizu, N., Yamaji, T., & Yu, W. (2005) Formation of multicellular epithelial structures. Novartis Found. Symp. 269:193-200.
O’Brien, L.E., Tang, K., Kats, E.S., Schutz-Geschwender, A., Lipschutz, J.H., & Mostov, K.E. (2004) ERK and MMPs sequentially reg- ulate distinct stages of epithelial tubule development. Dev. Cell 7:21-32. PDF
Yu, W., O’Brien, L.E., Wang, F., Bourne, H., Mostov, K.E., & Zegers, M.M. (2003) Hepatocyte growth factor switches orientation of polarity and mode of movement during morphogenesis of multicellular epithelial structures. Mol. Biol. Cell 14:748-763. PDF
Zegers, M.M., O’Brien, L.E., Yu, W., Datta, A., & Mostov, K.E. (2003) Epithelial polarity and tubulogenesis in vitro. Trends Cell Biol. 13:169-176. PDF
O’Brien, L.E., Zegers, M.M., & Mostov, K.E. (2002) Opinion: Building epithelial architecture: Insights from three-dimensional culture models. Nat. Rev. Mol. Cell Biol. 3:531-537. PDF
O’Brien, L.E., Jou, T.S., Hansen, S.H., Pollack, A.L., Zhang, Q., Yurchenco, P.D. & Mostov, K.E. (2001) Rac1 orients epithelial apical polarity through effects on basolateral laminin assembly. Nature Cell Biol. 3:831-838. PDF
Lipschutz J.H., O’Brien, L.E., Altschuler Y., Avrahami, D., Nguyen, Y., Tang, K., & Mostov, K.E. (2001) Analysis of membrane traffic in polarized epithelial cells. Curr. Protoc. Cell Biol. 15:Unit 15.5. PDF
O’Brien, L.E. & Mostov, K.E. (2001) Getting from here to there. Nature Cell Biol. 3:E116. PDF
Lipschutz, J.H., Guo, W., O’Brien, L.E., Nguyen, Y.H., Novick, P. & Mostov, K. E. (2000) Exocyst is involved in cystogenesis and tub- ulogenesis and acts by modulating synthesis and delivery of basolateral plasma membrane and secretory proteins. Mol. Biol. Cell 11:4259-4275. PDF