Integrating dynamic cell behaviors to drive cranial morphogenesis

About This Grant

Abstract Functional development of the body plan and organs requires tissues to adopt the specific three- dimensional morphologies required for function. Defects in tissue shape lead to functional deficits with impacts ranging from reduced or absent organ function to peri-natal lethality. The complex tissue shapes required for function are built from simple precursors by the spatially and temporally coordinated activity of individual cells. In many cases, final tissue shape is driven exclusively, or nearly exclusively by a single class of cell dynamic, such as cell shape remodeling, rearrangement of cells with respect to one another, or localized or oriented cell divisions. However, many tissues rely on a combination of multiple behaviors to build complex morphologies, which presents a challenge as these behaviors are incompatible within individual cells. Thus, a major challenge in human health and developmental biology is to understand how multiple classes of cell dynamics occurring concurrently in the tissue are successfully integrated despite their mutual antagonism in individual cells. A key related question is how these disparate behaviors are controlled and spatially patterned within tissues, as this spatial control is key to successful integration. In this proposal, we will use the mouse cranial neural plate as a model system for understanding how behaviors are integrated. This is an attractive system, as at least three mutually disruptive behaviors occur: apical constriction, planar polarized cell intercalation, and oriented cell divisions. We will use a combination of mouse genetics, bespoke cellular and subcellular live imaging approaches, quantitative in toto imaging of tissue organization, and a combination of molecular and transcriptomic approaches. Together, these experiments will directly define the role of each class of cell behavior in generating final tissue shape, elucidate the spatially delimited developmental signaling systems that control individual cell behaviors, and determine how mutually disruptive behaviors are integrated to drive complex tissue shape outcomes.