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Publications of the Week

Cilia Function as Calcium-Mediated Mechanosensors That Instruct Left-Right Asymmetry

By January 24, 2023No Comments

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This week we profile a recent publication in Science from the lab of Dr. Shiaulou Yuan (pictured) at Massachusetts General Hospital and Harvard Medical School.

Can you provide a brief overview of your lab’s current research focus?

We are a multidisciplinary group of biologists, biophysicists, and microscopists who aim to understand how fluid flows and biophysical forces shape the developing heart, and how these mechanisms underlie cardiac disease pathogenesis when gone awry. Specifically, we seek to illuminate how the cilium, a hair-like structure found on most cells in the human body, acts as an “antenna” to sense and translate extracellular signals into molecular processes that sculpt the early heart.

What is the significance of the findings in this publication?

How is left-right asymmetry of the human body determined? Although the human body is externally symmetric across the left-right axis, there are remarkable left-right asymmetries in the shape and positioning of most internal organs including the heart, lungs, liver, stomach, and spleen. Left-right asymmetry is specified during early embryogenesis by a small cluster of cells termed the left-right organizer. Within this organizer, motile cilia move rapidly to create a leftward directional flow of extracellular fluid that is the first sign of a left-right difference, but how this flow is sensed and transduced into later molecular and anatomical left-right asymmetry has been unclear. In this study, we uncover that immotile cilia in the organizer function as mechanosensors that translate biomechanics forces into calcium signals to sculpt the left-right body plan of the developing embryo.

Defects in left-right asymmetry are associated with numerous human disorders, including heterotaxy syndrome, primary ciliary dyskinesia, and congenital heart disease. Our findings represent a major advance in our understanding of the fundamental cellular mechanisms that underlie left-right asymmetry and open new avenues for the development of novel diagnostics for these disorders. Additionally, this work may pave the way for targeted therapies on cilia signaling and mechanosensing to improve outcomes. 

What are the next steps for this research?

Our future research seeks to illuminate the molecular mechanisms that govern ciliary mechanosensing. Further, we seek to develop new strategies to visualize and manipulate calcium signals in the cilium, with the long-term goal of developing novel tools for the diagnosis of cilia-associated disorders.

If you’d like to mention your funding sources, please list them.

This work was supported in part by the National Institutes of Health (Grants 1R35HL145249, 1K99HD086274, 1R01HL151704, and 1R01HL165241), American Heart Association (Grants 940516, 830304, and 969048), the Charles Hood Foundation, the Hassenfeld Foundation, the Gordon and Betty Moore Foundation (Grant 3396), and the National Science Foundation (Grant 1608744).

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