How epithelial cells polarize is still not fully understood. Some key principles have been proposed to maintain polarity, but the mechanisms behind these principles remain to be discovered. The first principle is
positive feedback. In computer models, a molecule that can be either membrane-associated or cytoplasmic can polarize when its association with the membrane is subject to positive feedback: that membrane localization occurs most strongly where the molecule is already most highly concentrated. In similar models, researchers have shown that epithelial cells can self-assemble into a rich set of robust biological shapes. In the yeast
saccharomyces cerevisiae, there is genetic evidence that Cdc42 is subject to positive feedback of this kind and can spontaneously polarize, even in the absence of an external cue. In the fruit fly
Drosophila melanogaster, Cdc42 is recruited by the aPKC complex and then promotes the apical localization of the aPKC complex in a probable positive feedback loop. Thus, in the absence of Cdc42 or the aPKC complex, apical determinants cannot be maintained at the apical membrane and consequently, apical identity and polarity is lost. The second principle is segregation of polarity determinants. The sharp distinction between apical and baso-lateral domains is maintained by an active mechanism that prevents mixing. The nature of this mechanism is not known, but it clearly depends on the polarity determinants. In the absence of the aPKC complex, the baso-lateral determinants spread into the former apical domain. Conversely, in the absence of any of Lgl, Dlg or Scrib, the apical determinants spread into the former baso-lateral domain. Thus, the two determinants behave as if they exert mutual repulsion upon one another. The third principle is directed
exocytosis. Apical membrane proteins are trafficked from the Golgi to the apical, rather than baso-lateral, membrane because apical determinants serve to identify the correct destination for
vesicle delivery. A related mechanism is likely to operate for the baso-lateral membranes. The fourth principle is lipid modification. A component of the lipid bilayer,
phosphatidyl inositol phosphate (PIP) can be phosphorylated to form PIP2 and PIP3. In some epithelial cells, PIP2 is apically localised while PIP3 is basolaterally localised. In at least one cultured cell line, the MDCK cell, this system is required for epithelial polarity. The relationship between this system and the polarity determinants in animal tissues remains unclear. ==Basal versus lateral==