Tissue tension in palate morphogenesis

University Of California, San Francisco, San Francisco CA

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Abstract

Project Summary Craniofacial morphogenesis is a highly dynamic, complex, and physical process that requires changes in the physical properties of cells and tissues, including their tension or stiffness, adhesion, and shape. Secondary palate morphogenesis is a multistage process involving complex behaviors of a heterogeneous mesenchyme. The palatal shelves undergo dramatic outgrowth and extension, followed by elevation, and later adhesion and fusion to form a continuous palatal structure. Failure of this process results in cleft palate, which occurs in around 1:1500 live births. However, this process is incompletely understood. Specifically, the changes that occur in the mechanical properties of the mesenchyme that give rise to complex morphogenetic behaviors during secondary palate development remain unclear. Actomyosin contractility generates mechanical force at the cellular level and underlies a wide array of processes including migration, shape changes, and regulation of cellular self-organization through regulation of cell-cell contacts. Actomyosin contractility is a critical component of tissue tension and shape, as well as a critical regulator of embryonic boundaries, restricting the intermingling of mesenchymal cell populations, to organize morphogenesis. Ephs and ephrins are key regulators of embryonic boundaries, with active signaling driving segregation between ephrin-expressing and Eph-expressing cells. Based on our previous studies, actomyosin contractility is likely to play an important role downstream of Eph/ephrin signaling in cell segregation and boundary formation. Both Ephs and ephrins and actomyosin contractility are known to play a critical role in palatal development; mice with mutations in Efnb1, or loss of EphB2 and EphB3 receptor function, and mice with mutations disrupting non-muscle myosin (NMII) contractility all exhibit cleft palate. Despite evidence for the importance of Eph/ephrin signaling and actomyosin contractility in the palate and in cellular organization, their influence on the cellular properties of palatal mesenchyme cells, and how this results in changes to secondary palate morphogenesis remains unknown. I hypothesize that actomyosin contractility drives boundary formation and changes in tissue tension to regulate tissue shape and secondary palate morphogenesis. Using primary palatal mesenchyme from NMII and EfnB1 mutants, I will analyze how actomyosin contractility influences cell contact and determine if cortical actomyosin contractility is driving cellular contacts and organization in the palatal mesenchyme. I will also test the role of NMII driven-actomyosin contractility in palate morphogenesis by analyzing palatal shape and tissue tension, and how these properties of the palate are affected by boundary formation. Completion of this work will enhance our understanding of normal and cleft palate morphogenesis by beginning to untangle how mesenchymal organization and tissue shape are regulated.