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Molecular Genetics and Cell Biology


Research Projects:

Epithelial Integrity

 
 

 

Two prominent characteristics of epithelial cells, apical-basal polarity and a highly ordered cytoskeleton, depend on the existence of precisely localized protein complexes associated with the apical plasma membrane, and a separate machinery that regulates the spatial order of actin assembly. ERM (Ezrin, Radixin, Moesin) proteins have been proposed to link transmembrane proteins to the actin cytoskeleton in the apical domain, suggesting a structural role in epithelial cells, and have been implicated in signaling pathways. Using genetic analyses we have shown that the sole Drosophila ERM protein Moesin functions to promote cortical actin assembly and apical-basal polarity. As a result, cells lacking Moesin lose epithelial characteristics and adopt invasive migratory behavior. Remarkably, our results also demonstrate that Moesin facilitates epithelial morphology by antagonizing activity of the small GTPase Rho. Thus, Moesin functions in maintaining epithelial integrity by regulating cell-signaling events that affect actin organization and polarity. Furthermore, our results have shown that there is negative feedback between ERM activation and activity of the Rho pathway.

Current studies are directed at understanding how ERM proteins regulate Rho function, and what the overall effects of misregulation of Rho function are in developing epithelia. In addition, we are studying coordinate regulation of Moesin and its close relative Merlin in proliferating epithelial cells.

 


Comparison between wild-type (left) and Moesin mutant (right) epithelia.
Green staining labels a stripe of cells in the epithelium. Normal cells with intact junctions and polarity do not intermix, as demonstrated by the highly coherent, intact stripe of labeled cells. In constrast, in an epithelium that lacks Moesin function, the labeled cells intermingle with unlabeled cells, indicating that epithelial integrity has been compromised.

 

 

Related publications:

McCartney BM, Fehon RG. Distinct cellular and subcellular patterns of expression imply distinct functions for the Drosophila homologues of moesin and the neurofibromatosis 2 tumor suppressor, merlin. J Cell Biol. 1996 May;133(4):843-52. (PubMed)

Bretscher A, Edwards K, Fehon RG. ERM proteins and merlin: integrators at the cell cortex. Nat Rev Mol Cell Biol. 2002 Aug;3(8):586-99. Review. (PubMed)

Speck O, Hughes SC, Noren NK, Kulikauskas RM, Fehon RG. Moesin functions antagonistically to the Rho pathway to maintain epithelial integrity. Nature. 2003 Jan 2;421(6918):83-7. (PubMed)

Fehon R. Cell biology: polarity bites. Nature. 2006 Aug 3;442(7102):519-20. (PubMed)

Hughes SC, and Fehon RG. Phosphorylation and activity of the tumor-suppressor Merlin and the ERM protein Moesin are coordinately regulated by the Slik kinase. J. Cell Biol. 2006 Oct 23;175(2):305-13. (PubMed)

Li Q, Nance MR, Kulikauskas R, Nyberg K, Fehon R, Karplus PA, Bretscher A, and Tesmer J. Self-masking in an intact ERM-merlin protein: an active role for the central alpha-helical domain. J. Mol. Biol. 2007 Feb 2;365(5):1446-59 (PubMed)

Hughes SC, Fehon RG. Understanding ERM proteins--the awesome power of genetics finally brought to bear. Curr Opin Cell Biol. 2007 Feb;19(1):51-6. Review. (PubMed)

Neisch, A. and Fehon, R.G. FERMing up the plasma membrane. Dev. Cell. 2008 14: 154-6. (PubMed)

McClatchey, A.I. and Fehon, R.G. Merlin and the ERM proteins - regulators of receptor distribution and signaling at the cell cortex. Trends Cell Biol. 2009 19: 198-206. (PubMed)

Fehon, RG, McClatchey, AI, and Bretscher, A. Organizing the Cell Cortex: The role of ERM proteins. Nat. Rev. Mol. Cell Biol. 2010 11: 276-287. (PubMed)

Hughes, SC, Formstecher, E., and Fehon RG. Sip1, the Drosophila orthologue of EBP50/NHERF1, functions with the sterile 20 family kinase Slik to regulate moesin activity. J. Cell Sci. 2010 123: 1099-107. (PubMed)

Neisch, A.L., Speck, O., Stronach, B., and Fehon, R.G. Rho1 regulates apoptosis via activation of the JNK signaling pathway at the plasma membrane. J. Cell Biol. 2010 189: 311-23. (PubMed)

Neisch, A.L. and Fehon, R.G. Ezrin, Radixin and Moesin: Key regulators of membrane-cortex interactions and signaling. Curr. Opin. Cell Biol. 2011 23: 377-82. (PubMed)

Neisch, A.L., Formstecher, E., and Fehon, R.G. Conundrum, an ARHGAP18 orthologue, regulates RhoA and proliferation through interactions with Moesin. Mol. Biol. Cell. 2013 24: 1420-1433. (PubMed)

Sherrard KM, Fehon R.G. The transmembrane protein Crumbs displays complex dynamics during follicular morphogenesis and is regulated competitively by Moesin and aPKC. Development. 2015 142: 1869-1878. (PubMed)

 

Fehon Lab Research Projects:

Septate Junctions  
Tissue Growth Control  

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