Orthologues of the serine/threonine kinase Par-1, a polarity determinant in the C. elegans one-cell embryo, have been identified as microtubule (MT)-regulating proteins in several systems. We have established that the mammalian PAR1-homologue EMK1 promotes the development of a non-centrosomal, apico-basolateral MT-array in kidney (MDCK) and hepatic (WIFB) epithelial cells at the time they are undergoing polarization. This change in MT-organization is essential for the generation of epithelial lumina, likely because of a key role of MTs in polarized targeting of luminal proteins. Kidney and liver epithelial cells differ in their lumen polarity and in the mechanisms they use to target luminal proteins. Kidney cells (e.g.MDCK) generate apical lumina and target proteins directly from the Golgi to the apical surface while hepatocytes form lumina at cell-cell contact sites (bile canaliculi) and target their luminal markers proteins by transcytosis via the basolateral domain. We have conclusively demonstrated that EMK1 -overexpression induced the appearance of intercellular lumina and an indirect apical targeting mode in MDCK cells. Thus, EMK1 is the first protein assigned the role of regulating the developmental branching decision between the hepatic and columnar epithelial phenotypes. The goals of this proposal are 1. to gain insight into the signaling mechanisms that underlie the role of the EMK1 in epithelial MT- and lumen organization and 2. to elucidate the EMK1 -mediated differences in the apical protein trafficking pathways that contribute to different lumen polarity in kidney epithelia and hepatocytes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Cellular and Molecular Biology of the Kidney Study Section (CMBK)
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Rasooly, Rebekah S
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Albert Einstein College of Medicine
Anatomy/Cell Biology
Schools of Medicine
United States
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Müsch, Anne (2018) From a common progenitor to distinct liver epithelial phenotypes. Curr Opin Cell Biol 54:18-23
Lázaro-Diéguez, Francisco; Müsch, Anne (2017) Cell-cell adhesion accounts for the different orientation of columnar and hepatocytic cell divisions. J Cell Biol 216:3847-3859
Akchurin, Oleh; Du, Zhongfang; Ramkellawan, Nadira et al. (2016) Partitioning-Defective 1a/b Depletion Impairs Glomerular and Proximal Tubule Development. J Am Soc Nephrol 27:3725-3737
Treyer, Aleksandr; Pujato, Mario; Pechuan, Ximo et al. (2016) Iterative sorting of apical and basolateral cargo in Madin-Darby canine kidney cells. Mol Biol Cell 27:2259-71
Lázaro-Diéguez, Francisco; Ispolatov, Iaroslav; Müsch, Anne (2015) Cell shape impacts on the positioning of the mitotic spindle with respect to the substratum. Mol Biol Cell 26:1286-95
Slim, Christiaan L; van IJzendoorn, Sven C D; Lázaro-Diéguez, Francisco et al. (2014) The special case of hepatocytes: unique tissue architecture calls for a distinct mode of cell division. Bioarchitecture 4:47-52
Müsch, Anne (2014) The unique polarity phenotype of hepatocytes. Exp Cell Res 328:276-83
Nachbar, Jeannette; Lázaro-Diéguez, Francisco; Prekeris, Rytis et al. (2014) KIFC3 promotes mitotic progression and integrity of the central spindle in cytokinesis. Cell Cycle 13:426-33
Ispolatov, Iaroslav; Müsch, Anne (2013) A model for the self-organization of vesicular flux and protein distributions in the Golgi apparatus. PLoS Comput Biol 9:e1003125
Slim, Christiaan L; Lázaro-Diéguez, Francisco; Bijlard, Marjolein et al. (2013) Par1b induces asymmetric inheritance of plasma membrane domains via LGN-dependent mitotic spindle orientation in proliferating hepatocytes. PLoS Biol 11:e1001739

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