The MyosinI system in Drosophila and zebrafish Left-Right asymmetry – DroZeMyo

The genetically controlled establishment of Left/Right (LR) asymmetry is a fundamental aspect of animal development, the importance of which is underscored by the fact that defects in the asymmetry of internal organs lead to severe pathologies. How symmetry is broken and how this translates into polarized, asymmetric morphogenesis are major open questions. In our collaborative project, we propose to use Drosophila and zebrafish to study the importance of MyosinID & C (MyoID/C) proteins for the establishment of LR asymmetry.

Pioneering studies in the mouse showed that motile cilia in the embryonic node create a directional fluid flow that is essential for body lateralization. While a ciliary fluid flow is essential for LR asymmetry in numerous vertebrates, this requirement is by no means universal. A particularly striking example is provided by Drosophila in which LR asymmetry is established without cilia. This raises the question whether different organisms use a variety of different mechanisms to establish LR asymmetry or whether a unifying underlying mechanism has yet to be identified? In this context it has been proposed that the chirality of cytoskeletal elements, in particular actin filaments, may provide an asymmetric template to promote laterality at the level of molecules, cells and entire organisms. Our project aims to use one invertebrate and one vertebrate model system to address whether Actin-binding MyoID/C proteins may represent a key element of a molecular system that is at the basis of LR asymmetry throughout animal evolution.

The function of MyoID in LR asymmetry was discovered by the team of partner 1 in the course of pioneering studies of LR asymmetry in Drosophila. MyoID acts as a unique dextral determinant expressed in tissue-specific LR organizers. The MyoIC paralog can in turn antagonize the activity of the MyoID determinant. A recent collaboration with the lab of partner 2 has allowed to show for the first time that the function of the MyoID/C system in LR asymmetry is conserved in zebrafish, extending hence the significance of this mechanism to vertebrate development. Here, the two collaborating labs propose to combine experimental approaches in Drosophila and zebrafish to address three major questions:

1. How is MyoID information translated into chiral morphogenesis ?
Work from partner 1 has revealed that Dachsous and Fat, two components of the global Planar Cell Polarity pathway, ensure the propagation of LR information from MyoID-expressing LR organizer cells to a target tissue undergoing chiral morphogenesis (hindgut). The molecular mechanism through which this is achieved remains however to be understood. We propose to address this issue using a combination of cell biological, biochemical and biophysical approaches.

2. What are the proteins that participate in the MyoID-dependent laterality program?
Our observations show that the MyoID/C system is of fundamental importance for the establishment of LR asymmetry in invertebrate and vertebrate organisms. Consequently, it will be crucial to identify additional components of this pathway. We will achieve this using the Drosophila hindgut as an in vivo model system to screen for novel factors involved in chiral morphogenesis.

3. How does the MyoID/C system contribute to the establishment of zebrafish LR asymmetry?
Unpublished data from partner 2 provide genetic evidence that MyoID is required for the formation and function of the zebrafish LR organizer. Using genetic, cellular and quantitative imaging approaches, we will determine the tissular and cellular functions of different components of the zebrafish MyoID/C system. In the light of our recent findings, particular attention will be devoted to the exploration of a potential implication of MyoI proteins in the PCP-dependent establishment of vertebrate LR asymmetry.