Cyclooxygenase signaling in neural crest migration and craniofacial development

About This Grant

Abstract/Summary Statement: The role of cyclooxygenase signaling in neural crest migration This proposed project aims to identify the role of cyclooxygenase (COX) signaling in regulating neural crest (NC) epithelial-to-mesenchymal transition (EMT), migration, and differentiation during embryonic development. NC cells are pivotal for forming diverse tissues in adult organisms and their dysregulation is linked to congenital anomalies like craniofacial clefts, jaw malformations, and congenital cranial neuropathy. The proposed research aims to reveal how COX signaling regulates NC EMT, migration, and differentiation by identifying which intracellular effectors link COX enzymes to cell state changes during NC EMT and migration, and how perturbation of COX signaling disrupts NC cell integrity, migration, and differentiation. By addressing these questions, we will uncover fundamental COX-mediated mechanisms driving NC cell development with implications for understanding craniofacial birth defects. Using the avian embryo model for its accessibility and developmental conservation with humans, Aim 1 will employ targeted gain- and loss-of-function experiments paired with RNA sequencing to delineate the intracellular effectors that bridge COX signaling with the NC gene regulatory network. In Aim 2, we will functionally characterize the impact of COX perturbation on NC cell integrity, migration, and subsequent differentiation into essential craniofacial and cranial peripheral nervous system components. We will pair functional perturbations with in situ hybridization chain reaction, immunohistochemistry, and high-resolution fluorescence imaging across various developmental stages to quantitatively characterize the craniofacial defects that occur after COX signaling modulation. Our preliminary findings indicate that COX inhibition inhibits NC migration and disrupts tissue formation, highlighting the critical role of COX-mediated pathways in development. The insights gained from this study will address a significant gap in our knowledge of the upstream regulation of EMT, thereby broadening our understanding of congenital birth defects and mitigating pathological EMT in adult diseases. Ultimately, this work will lay the foundation for future R01 applications that will dissect the COX signaling-dependent gene regulatory network to better identify potential therapeutic targets, driving translational advances that improve human health by targeting COX- dependent mechanisms in developmental contexts.