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Analysis of biomechanical mechanisms involved in left-right organizer morphogenesis
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Amack, Jeffrey
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Summer 2025
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2025-08
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Several internal organs are asymmetric along the left-right body axis. Disruptions of organ laterality can lead to birth defects including critical congenital heart defects. Organ laterality is controlled by the highly conserved transient left-right organizer (LRO). The zebrafish LRO, Kupffer's Vesicle (KV), is a ciliated organ necessary for left-right axis determination. To establish downstream organ laterality, KV must undergo remodeling to asymmetrically distribute its motile cilia along the anterior-posterior axis. After remodeling, 60% of cilia are found anteriorly and create a strong leftward flow of fluid within the KV lumen. This asymmetric leftward flow leads to the activation of genes identifying the left side of the embryo including the zebrafish Nodal homolog southpaw (spaw). If KV is unable to complete remodeling, defects in spaw expression and organ laterality can occur. The mechanisms involved in KV remodeling are poorly understood. Live imaging indicates that KV moves through the surrounding tailbud tissue as a speed greater than its surrounding environment. Mathematical modeling suggests that this movement imposes drag forces on KV that contribute to KV cell shape changes. Simulations identified the velocity of KV and the mechanical properties of the surrounding tailbud tissue as key modifiers of drag forces. In my thesis work, I tested the hypothesis that altering KV velocity or tailbud tissue dynamics that change drag forces on KV will disrupt remodeling of KV and subsequently lead to defects in left-right patterning of the embryo. In Chapter 2, laser ablations are used to disrupt tissues and cells implicated in KV velocity, and in Chapter 3 a photoactivatable Rho kinase inhibitor is used to alter actomyosin contractility in a targeted region of the tailbud tissue. Both approaches resulted in a significant decrease in KV velocity and defects in the AP asymmetric distribution of cilia in KV. However, only manipulations of the tailbud tissue resulted in laterality defects in the embryo. This work shows a role for biomechanical forces in KV remodeling in vivo and proposes the requirement of multiple biomechanical mechanisms in KV remodeling.
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