Cell adhesion molecules on the cell surface promote specific cell-cell interactions that direct the assembly of complex structures. In the visual system, both the retina itself and the visual circuitry must be precisely organized in order to accurately transmit visual information. Sidekicks (Sdks) are members of the immunoglobulin superfamily of proteins that have been implicated in specifying synaptic contacts in the vertebrate retina. Sdk-1 is also expressed in the developing kidney, where its upregulation contributes to the pathology of several disease conditions. Drosophila Sdk is required for photoreceptor axons involved in motion detection to organize their target tissue, the lamina. Sdk also shows a striking localization to other synaptic layers in the circuits that detect moving brightness increments or decrements. In epithelia such as the pupil retina, Sdk is specifically localized to contacts between three or more cells. The functions and expression patterns of Sdk overlap with those of Roughest (Rst) and Hibris (Hbs), two other immunoglobulin superfamily proteins homologous to mammalian NEPH1 and Nephrin, which form the slit diaphragm in the kidney. The goal of this proposal is to understand how Sdk interacts with these adhesion molecules to mediate specific cell contacts that organize visual system assembly.
The first aim will assess which cells in the visual circuitry express and require Sdk to form appropriate connections. The hypothesis to be tested is that Sdk expressed on neurons in the motion detection circuit contributes to the assembly of this circuit through homophilic interactions that define synaptic layers. The localization of Sdk to tricellular contacts suggests that it may also underlie the formation of the tetrad synapses characteristic of the visual system, which includes multiple postsynaptic cells.
The second aim will use loss of function and gain of function experiments to determine how Sdk acts at epithelial tricellular contacts to control the cell rearrangements that produce the highly ordered structure of the pupal retina.
The third aim will investigate how Sdk, Rst and Hbs influence each other's localization and function, in order to understand how these molecules act in combination to specify precise cellular contacts in the visual system. In addition, other proteins that contribute to Sdk function will be identified usinga genetic screen. These studies will provide insight into the molecular mechanisms that coordinate cell-cell interactions to assemble highly organized structures such as the visual circuitry and the kidney slit diaphragm.
Molecules on the cell surface guide specific cell-cell contacts that organize complex structures such as the visual system. We plan to investigate how Sidekick, a protein that is localized to contacts between three cells and to synapses between neurons involved in motion detection, helps to assemble a functional retina and visual circuit. We will also look at interactions between Sidekick and other adhesion molecules that have overlapping functions in the visual system and have been implicated in kidney disease.
| Astigarraga, Sergio; Douthit, Jessica; Tarnogorska, Dorota et al. (2018) Drosophila Sidekick is required in developing photoreceptors to enable visual motion detection. Development 145: |
