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Almost every eukaryotic cell can adopt a polarized subcellular organization. Cells use such polarized organization to migrate, to divide in a coordinate fashion, and to arrange themselves in multicellular structures. An excellent model to study cellular polarity is provided by epithelial cells. Epithelial cells interact with each other and form intercellular cavities (lumens) that are isolated from the environment in which the cells reside. The formation of such intercellular lumens is a fundamental step in the evolution of multicellular organisms as these lumens give rise to tubes that are crucial to ensure the transport of vital fluids and nutrients throughout organ systems of the organism. To put up specific functions at the different extracellular milieus, epithelial cells have segregated their surface into compositionally, functionally, and structurally distinct apical and basolateral domains that face the cavities and underlying tissues, respectively. Instrumental to the establishment of these distinct domains is the intracellular sorting and trafficking of proteins and lipids. Loss of epithelial cell polarity is correlated with diseases such as cancer, and defects in the ability of epithelial cells to correctly sort and/or target apical and basolateral molecules can be directly linked to the pathogenesis of human diseases including a. o. liver disease and microvillus inclusion disease.
General aim: to understand how epithelial cells develop and maintain apical-basolateral polarity.
Our focus: the epithelial cells’ apical surface. We want to know what are the cell biological principles that determine the polarized sorting and trafficking of proteins and lipids, and those that determine the development of apical surface domains and lumens.
1) Intracellular trafficking and dynamics of proteins and lipids in human hepatic cells
Defects in the ability of epithelial cells to correctly sort and/or target apical proteins and lipids, and to establish bile canaliculi, can be directly linked to the pathogenesis of human liver diseases. We focus on the distinct intracellular trafficking routes taken by different apical bile canalicular proteins, and the molecular mechanisms that underlie the sorting of these proteins in these routes. In addition to the Golgi apparatus as an intracellular sorting organelle, we have identified and highlighted in recent studies the involvement of the recycling endosome/ subapical compartment in the polarized trafficking of proteins and lipids and apical lumen development. Our current studies aim to understand the mechanisms that control polarized trafficking of proteins and lipids within the recycling endosomal system, and how endosomal trafficking controls apical surface and lumen development. We have recently identified the proton-sodium exchanger proton NHE6, which controls recycling endosome pH, as a novel regulator of polarized trafficking and, consequently, the maintenance of the apical bile canalicular surface, in hepatocytes (Ohgaki et al., Mol. Biol. Cell., 2010).
2) The pathogenesis of Microvillus Inclusion Disease
(In collaboration with Dr. Edmond H.H.M. Rings of the UMCG Dept of Pediatrics and the Beatrix Children’s hospital).
Microvillus inclusion disease is a rare congenital disorder that presents with persistent life-threatening secretory diarrhea shortly after birth and is characterized by structural and functional abnormalities of the small intestine epithelial brush border (i.e. apical surface). The pathogenesis of Microvillus inclusion disease remains unclear. The UMCG has recently performed two bowel transplants in children diagnosed with microvillus inclusion disease. We (Szperl et al., J. Pedriatic Gastroenterol. Nutr., 2010) and others have identified mutations in the gene encoding myosin Vb in microvillus inclusion disease patients. Interestingly, myosin Vb associates with recycling endosomes in most epithelial cells, where it regulates protein trafficking. These studies thus underscore the physiological relevance of recycling endosomes for epithelial polarity (Golachowska et al., Trends in Cell Biol., 2010). We currently study the consequences of disease-linked MYO5B mutations on recycling endosome function in enterocytes and other epithelial cells. These studies include tissue material from microvillus inclusion disease patients, model organisms and advanced three-dimensional epithelial cell culture systems.
3) Bile canalicular lumen biogenesis and morphogenesis
During in vivo liver development, newly formed intercellular lumens give rise to a network of bile canalicular tubes that is crucial to ensure the formation and transport of bile through the liver. This process has been proven difficult to reproduce outside the context of the in vivo liver. However, the ability to culture hepatocytes ex vivo with structural and functional liver-specific features is important for industry and clinic. We have recently reported that cultured human hepatocytes can self-induce bile canalicular lumen remodeling to form multicellular canalicular tubes through the deposition of extracellular matrix (Herrema et al., Mol. Biol. Cell., 2006). This provides a model system to understand the molecular mechanisms that underlie this complex process. We are currently studying the relationship between hepatocyte polarity, bile canaliculi development and cell division.
|Last modified:||November 19, 2012 09:43|