Rho Kinase and its effectors in PCP and development
Development and perpetuation of an organism depends on genetic programs that control the differentiation of distinct cell types and that orchestrate their morphogenetic behavior. They thus require the coordination of cellular polarity, movement, and shape, which are controlled by intercellular signals that are interpreted in a tissue-specific manner to coordinate the actin and microtubular cytoskeletons. Epithelia polarize across the tissue along the apical-basal axis, and within their plane (Planar Cell Polarity, PCP). Apical-basal polarization provides barrier function via tight junctions (TJ) and enables directional transport across a cell layer.
The cellular consequences of PCP signaling range from coordinated organization of cytoskeletal elements in single cells to complex migration of groups of cells and cell fate specifications. Examples of PCP in vertebrates can be very obvious, as in the ordered arrangement of scales on fish, feathers of birds, and hairs of mammalian skin. Less visible examples are the cilia of the lung and oviduct as well as the stereocilia of the sensory epithelium of the organ of Corti in the vertebrate inner ear. Furthermore, the complicated movement of mesenchymal cells during gastrulation (called convergence and extension) that leads to the elongation and thinning of the body axis also depends on correct PCP signaling. Failure PCP signaling can lead to left-right asymmetry defects, limb defects, ciliary diseases, deafness, and spina bifida.
PCP signaling is, however, best studied in Drosophila melanogaster, mainly because of the versatility of the fly as model system. In Drosophila, PCP can easily be seen on several external adult structures such as the bristles on the thorax or the precisely aligned hairs on wing cells. In addition, the facet eye also shows characteristics of PCP with its precise arrangement of each ommatidium. Genetic and molecular studies in Drosophila led to the identification of a highly conserved signaling network – the non-canonical Wnt/Frizzled-PCP pathway – directing PCP establishment. Due to the available tools and the possibility to use a combination of genetic and biochemical approaches, Drosophila is ideally suited to further dissect the PCP pathway and define its relationship to the cytoskeleton. Rho kinase (Rok aka Rock) is a critical hub coordinating cellular (PCP) signaling with tissue-specific outputs such as modification of the actin cytoskeleton. We have performed a genome wide substrate screen for novel Rho kinase substrates and are currently using genetic and molecular approaches to address their function. Most recently, we found evidence for Rok and its substrate Combover affecting spermatogenesis.
Understanding how Rok and its substrates affect cellular behavior during development is a necessary step toward understanding how Rok interfaces with diverse cellular responses critical for organogenesis. Given the reiterative use of morphological mechanisms in organisms as diverse as flies and mammals, characterizing these novel Rok substrates and determining the mechanisms by which they contribute to development will shed light on related morphogenetic processes in humans.
