What prevents us from growing six eyes, or nine, instead of just two? Why do millions of regenerating planarians look the same, even though they are growing new tissues? The answer: cell signaling! We are interested in how regenerating tissues know what shape to form, which will provide strategies to help regenerative medicine replace lost organs or limbs.
Above: A worm whose cell-to-cell (gap junction) communication was blocked during regeneration, so each of its four wounds grew a head.
Shape is essential…from proteins to organisms. Shape changes and tissue remodeling drive development, disease and even aging. But despite the importance of shape, we still know very little about how shape is established, maintained, and (following injury) restored. Although recent advances have enabled us to determine developmental pathways and cell fate mechanisms, this still does not explain how changes in individual cells lead to an animal’s gross anatomy. So the main questions remain. Why do babies all have that stereotypical “human” shape (and never look like frogs or fish or birds)? How does that human embryo know what “human” should look like, anyway? Our research uses planaria as a model of regenerative shape. Planarians have great plasticity (the ability of tissues to be reshaped) and yet are normally resistant to malformations during regeneration. However, by disrupting cell signaling in the lab, we can regenerate new worms that are wildly misshapen.
The restoration of shape during planarian regeneration requires very sophisticated coordination between new and old tissues, in order to align pre-existing organs with the newly formed ones. Our data reveal that membrane depolarization (mediated by the H,K-ATPase ion transporter) is upstream of both head formation and the anterior identity of new tissues (which drives new tissue shape), as well as apoptotic-mediated tissue remodeling in pre-existing tissues. If H,K-ATPase activity is only partially knocked-out, regenerates are able to form heads, but lack the ability to shape pre-existing tissues, failing to maintain overall body shape (image to the right). The resulting worms have tiny, shrunken heads and anteriorly shifted, abnormally large pharynges. Our overall goal is to determine how changes in voltage at the plasma membrane can coordinate overall animal shape in both new and old tissues.
Above: Control (bottom center) and H,K-ATPase inhibited (remaining) regenerates illustrate the changes in head shape when membrane voltage is altered.