Associate Professor Shanghai Tech Shanghai, Shanghai, China
Abstract: All organs require the controlled growth of stem and progenitor cells to scale the structure to the correct size with the body. While many growth factors and morphogens are known that control growth, it remains unclear how these mechanisms are coordinated to scale entire anatomical structures. Findings from several labs show that endogenous cell electrophysiology controls proportional growth of entire anatomical structures. We have uncovered how the K+-leak channel Kcnk5b (which decreases intracellular K+) scales proportional growth and how this electrophysiological mechanism can be regulated. The developmental mechanisms and the organization of gene expression patterns of all early embryonic mouse and human limbs are conserved in the development of the pectoral fin bud of the zebrafish embryo. Using fin bud as a model for early vertebrate fin/limb development, we observed coordinated decreases in endogenous intracellular K+ levels during bud outgrowth of the entire mesenchyme and ectoderm tissues, and overexpression of the different K+-leak channels is sufficient to increased bud size of the entire anatomical structure by enhancing the transcription of the morphogens that control bud development. We subsequently found that Kcnk5b-regulated scaling requires cell-autonomous IP3R-mediated Ca2+ release from the endoplasmic reticulum and CaMKK activity to regulate the transcription of shh, a morphogen that is itself required and sufficient to alter proportional growth. We also found that retinoic acid (RA), a hormone morphogen from the body, reduces intracellular K+ throughout the fin bud and that RA regulates Kcnk5b activity by dephosphorylation of serine 345 in its cytoplasmic tail via Rcan2-calcineurin signal transduction. Finally, we determined that this mechanism is also involved in scaling the growth of adult regenerating fins. Together, our findings show how a growth promoting hormone (RA) from the body decreases intracellular K+ and how this electrophysiological change controls a Ca2+-mediated signal transduction to regulate the transcription of shh in order to scale the proportions of entire anatomical structures.
Funding Source: ShanghaiTech University and National Science Foundation of China
