Instructor in Medicine, Massachusetts General Hospital

Lydia Djenoune, Ph.D.

Going with the flow: Cilia and Polycystins in Left-Right Patterning

In most vertebrates, the left-right (LR) body axis is specified during early embryogenesis by a cluster of cells in the left-right organizer. In this structure, motile cilia move rapidly to create a leftward directional flow of extracellular fluid that first breaks bilateral symmetry in the developing embryo. However, how this flow is sensed and transduced into phenotypic LR asymmetry remains unclear. By developing and utilizing a novel optical toolbox that combines light sheet microscopy, optical tweezers, genetically encoded calcium indicators, and deep learning, we show that immotile cilia function as mechanosensors that convert flow forces into calcium signals that rely on Polycystin channels. The mechanical manipulation rescues cardiac laterality in zebrafish and is instructive: left- or right-sided cardiac looping is induced by targeting one cilium on the left or right side of the organizer, respectively. Our results establish cilia as mechanosensitive cellular levers that convert biomechanical forces into calcium signals that build the LR axis and present a model to decipher mechanisms leading to proper left-right asymmetry.