The Planar Cell Polarity (PCP) proteins are a highly conserved molecular system for coordinating cells within a sheet, and in vertebrate animals, these proteins control collective cell movements termed convergent extension. This proposal seeks to address two key outstanding issues in vertebrate PCP biology. 1) Actomyosin contraction is the key driver of most cell movements, but surprisingly little is yet known about th links between PCP proteins and actomyosin contraction, especially in vertebrates. We will determine the role of PCP proteins in controlling the spatial and temporal patterns of Myosin II activation in cells engaged in convergent extension. We will combine live imaging approaches and laser-microdissection to investigate cell shape changes, dynamic protein localization, and cell cortex tension during convergent extension. 2) The dynamic localization of PCP proteins is central to their normal function, but how these proteins are localized during convergent extension and how their localization drives collective cell movements in unknown. We will use live imaging new fluorescent reporters to address this issue during vertebrate gastrulation. Impact: PCP-mediated convergent extension is essential for neural tube closure, and mutations in PCP genes can be causative for human birth defects that result from failure of neural tube closure. The experiments proposed here will thus inform our understanding human neural tube defects such as spina bifida. In addition, recent data now suggest a role for PCP-dependent convergent extension in the morphogenesis of kidney tubules, so experiments proposed here will shed new light on mechanisms underlying congenital polycystic kidney disease.
This study centers on a set of proteins called the planar cell polarity (or PCP) proteins and the mechanism by which they govern cell movements called convergent extension. These experiments will be significant because PCP proteins and convergent extension are essential for neural tube closure, and failure of these movements' results in class human birth defects called 'neural tube defects,' which include spina bifida and anencephaly. In addition, recent data now suggest a role for PCP proteins and convergent extension in the kidney tubules, so experiments proposed here will shed new light on mechanisms underlying congenital polycystic kidney disease.
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