Wednesday, May 8, 2024
5/8/2024
Summary/Abstract Planar cell polarity (PCP) signaling controls the polarization of cells within the plane of an epithelium, orienting asymmetric cellular structures, cell divisions, and cell migration and is well conserved from Drosophila to vertebrates. In vertebrates, defects in the core PCP mechanism result in a range of developmental anomalies and diseases including conotruncal heart defects, open neural tube defects, deafness, and situs inversus and heterotaxy, among others. Congenital heart disease (CHD) comprises close to half of all birth defects, and conotruncal heart malformations are the most common CHDs in humans, and include anomalies such as double outlet right ventricle, transposition of the great arteries, and overriding aorta. Despite its critical role in the development of the heart and other organs, the molecular mechanisms that drive PCP signaling remain remarkably poorly understood. Although a mechanistic dissection of PCP signaling would be prohibitively difficult in the mammalian heart, mechanistic conservation in PCP signaling allows findings from highly tractable model systems to translate readily to PCP in mammalian systems. Drosophila is an ideal system for studying PCP due to its highly developed genetic tools, its history as a PCP model system, and its suitability for high-resolution microscopy. In this project, we will leverage the experimental tractability of the Drosophila model system, in combination with cutting-edge biochemical and biophysical approaches, to elucidate the mechanistic basis for PCP signaling. We propose two independent but interrelated Aims that will i) elucidate the feedback circuits and molecular interactions that lead to the induction of asymmetry, and ii) determine how clustering contributes to the amplification of asymmetry, to polarity readout, or both. To accomplish this, we will employ novel genetic approaches to unlock understanding of extensive feedback mechanisms in PCP signaling, single-molecule biophysical approaches that will reveal how clustering is coupled to the amplification and readout of asymmetry, and advanced biochemical approaches that will provide direct molecular insight into how intrinsic asymmetry in PCP complexes is achieved and into how oligomerization may result in clustering. The proposed work will both enhance our knowledge of fundamental mechanisms underlying PCP signaling, as well as lay the groundwork for potential therapeutic interventions for PCP-related heart pathologies.
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