We are  elucidating molecular mechanisms that determine morphology and polarity of epithelial cells.

Specifically, we are addressing an unresolved key question in liver development and liver regeneration after injury, namely how the liver’s parenchymal epithelial cells, the hepatocytes, acquire an epithelial architecture that is unique among epithelia and is superbly adapted to their functions: Unlike most epithelia, which organize as monolayered ducts or acini, hepatocytes arrange in cords aligned along fenestrated blood vessels on either side and with a capillary-like luminal network (bile canaliculi) running between. This organization facilitates their extensive bi-directional molecular exchange with the blood, while allowing bile acid excretion into the bile canaliculi. How this remarkable hepatocyte polarity phenotype arises has remained largely unknown.

To tackle this question, we generated a novel cell line in which polarity can be switched from ductal to hepatocytic. This tool allowed us to identify Extracellular Matrix (ECM)- and Cell-cell adhesion signaling as critical determinants for the hepatocytic versus ductal polarity decision. We are currently elucidating, in primary hepatocyte cultures, the mechanisms underlying the roles of these adhesion systems for bile canaliculi formation.

The unique polarity phenotype of hepatocytes is accompanied by a unique organization of their biosynthetic protein trafficking itineraries, the pathways by which apical and basolateral proteins are delivered to their respective surface domains. We are investigating the molecular basis for the hepatocyte-specific targeting of apical proteins to their bile canalicular domains, with the goal of understanding if hepatocytic trafficking itineraries and -morphology are contingent on each other.

Selected Publications:

Lázaro-Diéguez F, Müsch A. (2022). Live-cell Imaging of Biosynthetic Protein Transport in   Hepatocytes. In: Tanimizu, N. (eds) Hepatocytes. Methods in Molecular Biology, vol 2544.  Humana, New York, NY. https://doi.org/10.1007/978-1-0716-2557-6_10

Lázaro-Diéguez F, Müsch A. Low Rho activity in hepatocytes prevents apical from basolateral cargo separation during trans-Golgi network to surface transport. Traffic 2020 May;21(5):364-374

Lázaro-Diéguez F, Müsch A. “ Cell-cell adhesion accounts for the different orientation of columnar and hepatocytic cell divisions”, J Cell Biol. 2017 216(11):3847-3859.

Treyer, A., Pujato, M, Pechuan, X and Müsch, A. “Iterative sorting of apical and basolateral cargo in MDCK cells”. Mol. Biol. Cell  2016 27(14):2259-71

Lázaro-Diéguez F, Ispolatov I, Müsch A. Cell shape impacts on the positioning of the mitotic spindle with     respect to the substratum. Mol Biol. Cell, 2015,. Apr 1;26(7):1286-95

Lazaro-Dieguez, F. Cohen D., Fernandez D., Louis Hodgson, S. van IJzendoorn and Müsch, A. “Par1b links lumen polarity with LGN/NuMA positioning for distinct epithelial cell division phenotypes”, (2013) J Cell Biol. 203(2): 251-64

Ispolatov I, Müsch, A. " A model for the self-organization of vesicular flux and protein distributions in the Golgi apparatus", (2013), PLOS Computational Biology, Jul;9(7):e1003125. doi: 10.1371/journal.pcbi.1003125

Cohen D., Fernandez D., Lazaro-Dieguez, F. and Anne Müsch,. “The serine/threonine kinase Par1b regulates epithelial lumen polarity via IRSp53-mediated cell-ECM signaling”, (2011) J Cell Biol. 192, 525-540.

Cohen, D., Rodriguez-Boulan, E. and  Müsch, A. (2004). "Par-1 promotes a   hepatic mode of apical protein trafficking in MDCK cells". PNAS 101, 13792-97.

Cohen, D., Brennwald, P.J., Rodriguez-Boulan, E.  and Müsch, A.  (2004)."Mammalian PAR-1 determines epithelial lumen polarity by organizing the microtubule cytoskeleton". Journal Cell Biology, 164, 717-727.

Zamperone A, Cohen D, Stein M, Viard C, Müsch A. Inhibition of polarity-regulating kinase PAR1b contributes to Helicobacter pylori- inflicted DNA Double Strand Breaks in gastric cells. Cell Cycle. 2019 Feb;18(3):299-311.

Mishra JP Cohen D, Zamperone A, Nesic D, Muesch A, Stein M. CagA of Helicobacter pylori interacts with and inhibits the serine-threonine kinase PRK2. Cellular microbiology. 2015; 17(11):1670-82.

Zaher Zeaiter, David Cohen, Anne Müsch, Fabio Bagnoli, Antonello Covacci, and Markus Stein (2008) "Analysis of detergent resistant membranes of Helicobacter pylori infected gastric adenocarcinoma cells reveals a role for MARK2/Par1b in CagA-mediated disruption of cellular polarity",  J Cellular Microbiology, 10, 781-94.

Reviews and Book Chapters:

Müsch A. and  Arias I “Hepatoyte Surface Polarity” in:  The Liver: Biology and  Pathobiology,  Sixth Edition, Edts: Arias et al., 2020 Print ISBN:9781119436829 Wiley &Sons Ltd

Müsch, A. 2018. From a common progenitor to distinct liver epithelial phenotypes. Current opinion in cell biology. 54:18-23.

Müsch, A. Vesicular Transport in the Secretory and Endocytic Pathways, e-book in Colloquim Series on Building Blocks of the Cell: Cell Structure and FunctionMorgan & Claypool Life Sciences September 2014, 125 pages, (doi:10.4199/C0011ED1V01Y201407BBC008)

Müsch, A. “The unique  polarity phenotype of hepatocytes” Exp. Cell Research 2014. 328(2):276-83.

Treyer A., Müsch, A. “Hepatiocyte Polarity” , (2013) Comprehensive Physiology, 3, 243-87.

Rodriguez-Boulan, E., Kreitzer G and Müsch, A.  (2005) "Protein Sorting and Post-Golgi Trafficking in Epithelia."Nature Reviews Molecular Cell Biology, 6, 233-47

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