Description of Research Expertise

Research Interests
Tubular organ development in C. elegans

Key words: C. elegans, signal transduction, Ras, genetics, tube development.

Description of Research
During embryonic development, multipotent cells must choose among various possible fates, and then differentiate and join together with appropriate neighbors to form functional organ systems. My research utilizes the “excretory” or renal system of the nematode worm Caenorhabditis elegans as a model system for studying the formation of tubular organs. C. elegans has many advantages for such studies, including a very simple and well described anatomy that allows phenotypic analysis at a single-celled resolution – for example, the worm’s renal system consists of only three connected single-celled tubes! C. elegans also has a sequenced genome containing many of the same genes found in more complex organisms, and it is highly amenable to powerful forward and reverse genetic approaches to find genes involved in a process of interest. We are identifying genes important for cells to adopt renal fates, form unicellular tubes and connect with one another to form a functional renal conduit, as well as genes that modulate the signal transduction pathways that control these processes.

Ras signaling, Notch signaling and cell fate specification
Both the EGFR/Ras/ERK and Notch signaling pathways play important roles in specifying excretory system cell fates. These pathways also are used to control many other developmental events, and a major question concerns the downstream targets of these pathways, how cell-type appropriate targets are chosen, and how these targets act with other cell intrinsic factors to elicit specific responses. The lab has identified and is characterizing a number of potential ERK targets important for excretory duct cell fate specification, as well as scaffold proteins that modulate signaling in a cell-type specific manner.

Lipocalin signaling and tubular morphogenesis
The tubular cells of the excretory system are an excellent model for studying mechanisms of intracellular lumen formation and tube connectivity. Through genetic screening, we discovered a lipocalin-dependent signaling mechanism that controls lumen connectivity. Lipocalins are secreted cup-shaped proteins that bind sterols, odorants and other small lipophilic molecules and deliver them to target cells via specific plasma-membrane bound receptors. Studies are underway to identify the signaling pathway and cellular mechanism through which the LPR-1 lipocalin is acting. These studies are likely to be relevant to development of capillaries in the mammalian microvasculature, which are also networks of single-celled tubes.

Epithelial junction integrity and remodeling
The tubular cells of the excretory system are also an excellent model for studying junction formation and remodeling. These cells undergo de novo epithelialization and junction formation during tubulogenesis, and the excretory pore cell later undergoes a programmed withdrawal and loss of epithelial identity. We identified a family of apically localized transmembrane "eLRRon" proteins that are required to organize the apical extracellular matrix and maintain junction connectivity. Current studies are examining the link between matrix and junctions, and testing whether modulation of eLRRon activity contributes to programmed junction remodeling.

Rotation Projects
Please see Meera about possible projects

Lab personnel:
Gregory Osborn, graduate student (jointly supervised with John Murray)
Michelle Kanther, postdoctoral fellow
Jean Parry, postdoctoral fellow
Emily Pu, postdoctoral fellow
Jennifer Cohen, research specialist
Hasreet Gill, undergraduate assistant
Julian Bello, undergraduate assistant