Team work for tissue growth
During animal development, a set of life-sustaining chemical reactions, called metabolic reactions, provide the fuel and molecular building blocks to power tissue growth. However, metabolic reactions are not enough to create a tissue of a given size, shape, and pattern. In addition, special cell-to-cell signaling pathways are required, where molecules, called morphogens, are secreted from one part of the tissue to control gene expression throughout the tissue. Accumulating evidence in tumor biology suggest that morphogens influence cell metabolism of malignant tissues. However, the connection between morphogen signaling and the metabolic reactions underlying tissue growth during development is not well understood.
The Dye / Eaton research lab, headed by Natalie Dye, together with the research lab of André Nadler, both located at the MPI-CBG, set out to investigate this connection. They studied the Hedgehog pathway, which is conserved from flies to humans and regulates the growth and patterning of many animal tissues during development. The first author Stephanie Spannl, a former PhD student of the lab, describes the results: “We found that inhibiting glycolysis, a series of reactions that break down glucose into smaller metabolites to produce energy and precursors for many proteins and nucleotides, causes an increase in the activity of the Hedgehog signaling pathway, both in flies and in vertebrates. Using the fly model, we discovered that glycolysis is required to maintain the plasma membrane potential and that perturbation of this potential alters the cellular uptake of specialized lipids that regulate the activity of the Hedgehog pathway.”
Natalie Dye, corresponding author of the study, summarizes: “Our work provides novel insight into the fundamental mechanisms connecting two key aspects of growth regulation: morphogens and metabolism. Misregulation of either of these types of pathways have been linked to disease conditions, in particular cancer. As has been demonstrated many times, studying developmental growth can help us discover how growth can be deregulated in cancer. Our work provides a molecular mechanism, demonstrating how the Hedgehog signaling pathway and metabolism are inter-connected.”
Stephanie Spannl, Tomasz Buhl, Ioannis Nellas, Salma A Zeidan, K Venkatesan Iyer, Helena Khaliullina, Carsten Schultz, André Nadler, Natalie A Dye, Suzanne Eaton: Glycolysis regulates Hedgehog signalling via the plasma membrane potential. The EMBO Journal. 6. October. doi: 10.15252/embj.2019101767