Ciliated epithelia produce directed fluid flow that is critical for human organ formation and function. One of the key outstanding questions in the field is how these epithelia acquire a planar axis required for cilia orientiation or positioning, thus directing ciliary flow in an appropriate way for function. This issue is particularly important in the context of the left-right patterning, where a flow-based mechanism operates within a structure called the left-right organizer (LRO). Flow produced in the LRO breaks symmetry along the left-right body axis, and defects in this process is thought to be a leading cause of heterotaxy in humans, including in the etiology of congenital heart defects. To achieve flow-based patterning, cilia are positioned along the anterior-posterior (A-P) planar axis of LRO cells, causing a tilt that results in leftward flow but how this axis is initially aligned to the A-P body axis is unknown. Recently, mechanical strain has emerged as an important global cue that directs the axis of planar polarity in epithelia with multiciliated cells, raising the possibility that mechanical cues also direct the formation of the LRO. Indeed, in preliminary studies, mechanical strain was found to not only pattern the planar axis of the Xenopus LRO, but also the formation of motile cilia, and cilia location. The impact of mechanical strain on the LRO will be studied using imaging approaches and experimental manipulations that perturb the patterns of strain in the embryo. Together, these studies will provide new insights into how mechanical strain can act as a multifaceted cue to direct key features required for flow-based patterning of the left-right axis, and how mechanical perturbations in the embryo can lead to birth defects.

Public Health Relevance

All ciliated epithelia generate directed fluid flow by employing a planar axis to orient or position their motile cilia, but how this planar axis is established remains poorly understood. The proposal will test the role of mechanical strain as a graded patterning cue in establishing a planar axis within a structure, called the left-right organizer (LRO), where left-right symmetry is broken in the early embryo by leftward flow. These studies will determine how mechanical strain is a potent multifaceted cue required for left-right patterning and how perturbation in strain can affect embryonic development, leading to birth defects.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD092215-02
Application #
9534171
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mukhopadhyay, Mahua
Project Start
2017-08-01
Project End
2022-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Salk Institute for Biological Studies
Department
Type
DUNS #
078731668
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Kim, Seongjae; Ma, Lina; Shokhirev, Maxim N et al. (2018) Multicilin and activated E2f4 induce multiciliated cell differentiation in primary fibroblasts. Sci Rep 8:12369
Chien, Yuan-Hung; Srinivasan, Shyam; Keller, Ray et al. (2018) Mechanical Strain Determines Cilia Length, Motility, and Planar Position in the Left-Right Organizer. Dev Cell 45:316-330.e4
Chien, Yuan-Hung; Keller, Ray; Kintner, Chris et al. (2015) Mechanical strain determines the axis of planar polarity in ciliated epithelia. Curr Biol 25:2774-2784