Harvard University COVID-19 updates

Department News



Stephen Von Stetina (l) and Susan Mango

Polarity is all around us – in our batteries, in our politics, and most beautifully in our cells. Cell polarity is a fundamental process in multicellular organisms and allows for the compartmentalization of specialized domains at different parts of the cell. Epithelia epitomize this notion, as their function as barriers and transporters of fluids and gases requires them to be highly polarized. A typical epithelial cell has an apical side that faces the free or lumenal surface and a basolateral domain that contacts a basement membrane. Think of your intestinal epithelium – the apical surface, specialized as a microvillus, expresses receptors to bring nutrients into the cell (and transport them across the cell to the basal surface and then the bloodstream), but also acts as a barrier to keep bacteria and other toxins from entering the body. Imagine then if this tissue organization was disrupted! This phenomenon is exactly what happens in maladies such as Crohn’s disease or ulcerative colitis. In addition, epithelia are the most abundant cell type in the body, and thus most cancers are of epithelial origin. Advanced states of cancer are correlated with a disruption in tissue organization and a loss of cell polarity, which can lead to metastasis.
Years of work, mainly from cell culture, suggested that epithelia require spatial cues, dubbed outside-in signals, in order to polarize. These cues can come from cell-cell or cell-substratum interactions, and are thought to be mediated by the adhesion molecules E-cadherin or b-integrin, respectively. Recent work from model organisms and cell culture has begun to dispute this dogma, however. For example, a single intestinal cell cultured in the absence of adhesive contacts has an amorphous shape, but can be strikingly polarized upon the activation of a polarity kinase within the cell – no contacts needed. In certain mammalian tissues, inactivation of either the cadherin pathway or the integrin pathway resulted in no abnormalities in epithelial polarity. However, it remained formally possible that inactivation of either pathway was insufficient to induce a phenotype in vivo – that is, removal of the cadherin pathway could be compensated by the integrin pathway, or vice versa. Studying this potential redundancy in mammalian systems is hard, because there are multiple cadherin and integrin proteins. However, in the nematode Caenorhabiditis elegans, there is only one E-cadherin and one b-integrin homolog, making it an ideal system to test this hypothesis.
In an article published in Developmental Biology, Stephen Von Stetina and Susan Mango generated mutant C. elegans embryos that lacked both cadherin and integrin function and analyzed markers of epithelial polarity. Nematodes have four embryonic epithelia: the epidermis (skin), the foregut, the midgut/intestine, and the arcade cells (which link the foregut to the epidermis). Intriguingly, cell polarity was intact in all four epithelia in the cadherin-integrin double mutant embryos. This suggested that the dogmatic view – that outside-in signaling mediated by cadherins and integrins – was dispensable in this animal.
What then, is important? The researchers focused on the arcade cell epithelium and queried whether a known regulator of cell polarity, the PDZ protein PAR-6, was important for epithelium formation. In other epithelia, par-6 mutants have polarized localization of apical and junctional proteins, but they fail to form continuous. However, the arcade cells exhibited a more severe phenotype: lack of polarized localization for apical and junctional markers.
In sum, these results show that there is not a ‘generic’ polarity pathway that is used in all epithelial cells. In other animals, many epithelia can still polarize when cadherin or integrin are disrupted, suggesting that alternative pathways for epithelium formation may be generally true. C. elegans is a powerful system to elucidate these other mechanisms.
Read more in Developmental Biology or download PDF

View Susan Mango’s Faculty Profile