Jeffrey Hildebrand

How is it that cells manage to regulate their shape and organization during embryonic development in order to form the various tissues and diverse body plans seen in adult organisms? 

In most circumstances, cells utilize the coordinated efforts of signaling pathways, effector proteins, cytoskeletal networks, and contractile myosins to elicit the changes in cell morphology needed to form tissues and structures with beautiful and elaborate architecture.  Understanding the regulation and integration of these cellular components, pathways, and networks in these fascinating processes is the main objective of the work in the Hildebrand lab.  We use a variety of genetic, cellular, biochemical, molecular, and structural approaches to understand how cell and tissue morphology is regulated.  We are currently studying the function and regulation of the Shroom family of proteins as a model to understand these processes.

Using numerous in vivo and in vitro model systems and approaches, we have shown that Shroom proteins are a family of actin-associated scaffolding molecules that control cellular architecture and tissue morphology during processes such as neural tube closure (Figure 1), kidney formation, vascularization (Figure 2), and Drosophila tissue morphogenesis (Figure 3).To date we have characterized the functions of vertebrate Shroom2, 3, and 4 and the ortholog of Shroom, from Drosophila melanogaster.  It appears that all Shroom proteins control cell and tissue architecture by regulating the distribution of contractile actomyosin networks. 

This activity is dependent on the ability of Shroom proteins to bind and recruit Rho-kinase, an activator of non-muscle myosin II, to specific regions of the cell. Once recruited, we hypothesize that Rock locally activates myosin II and subsequently changes or regulates cell contractility or shape.

The current work in our lab endeavors to understand the molecular, biochemical, and cellular basis for how Shroom proteins control actomyosin networks.  In addition, we are trying toelucidate how different types of contractile networks are assembled in a cell and what outcomes these different types of networks may have on cell behavior and tissue morphology.  Finally, we are using cellular and genetic analysis to define other players in the Shroom network and identify other pathways that cooperate with Shroom to control cellular behaviors.