Abstract
The orderly packing and precise arrangement of epithelial cells is essential to the functioning of many tissues, and refinement of this packing during development is a central theme in animal morphogenesis. The mechanisms that determine epithelial cell shape and position, however, remain incompletely understood. Here, we investigate these mechanisms in a striking example of planar order in a vertebrate epithelium: The periodic, almost crystalline distribution of cone photoreceptors in the adult teleost fish retina. Based on observations of the emergence of photoreceptor packing near the retinal margin, we propose a mathematical model in which ordered columns of cells form as a result of coupling between planar cell polarity (PCP) and anisotropic tissue-scale mechanical stresses. This model recapitulates many observed features of cone photoreceptor organization during retinal growth and regeneration. Consistent with the model's predictions, we report a planar-polarized distribution of Crumbs2a protein in cone photoreceptors in both unperturbed and regenerated tissue. We further show that the pattern perturbations predicted by the model to occur if the imposed stresses become isotropic closely resemble defects in the cone pattern in zebrafish lrp2 mutants, in which intraocular pressure is increased, resulting in altered mechanical stress and ocular enlargement. Evidence of interactions linking PCP, cell shape, and mechanical stresses has recently emerged in a number of systems, several of which show signs of columnar cell packing akin to that described here. Our results may hence have broader relevance for the organization of cells in epithelia. Whereas earlier models have allowed only for unidirectional influences between PCP and cell mechanics, the simple, phenomenological framework that we introduce here can encompass a broad range of bidirectional feedback interactions among planar polarity, shape, and stresses; our model thus represents a conceptual framework that can address many questions of importance to morphogenesis.
Highlights
Epithelia are one of the basic building blocks from which animals sculpt complex tissues and organs during development [1,2,3,4,5]
We introduce a mathematical model in which anisotropic, tissue-scale mechanical stresses interact with intrinsic planar cell polarity (PCP) in cones to generate cell packing in a rectangular lattice with long-ranged order
To identify the cells whose apical profiles are delimited by Zonula Occludens-1 (ZO-1) we used several transgenic zebrafish lines in which fluorescent reporters are driven by cell-specific promoter sequences: sws1 for ultraviolet cones [51], sws2 for blue cones [21]; cone alpha-transducin for all cones [52], rh1 for rod photoreceptors [53]; and gfap for Muller glia [25]
Summary
Epithelia are one of the basic building blocks from which animals sculpt complex tissues and organs during development [1,2,3,4,5]. The neural retina exhibits a high degree of epithelial organization, both in the radial direction, where it comprises multiple, stratified layers, and within layers, where the spatial distribution of each class of neuron within the epithelial plane has consistently been shown to be non-random [10]. This planar order is especially pronounced in adult teleost fish, where the cone photoreceptor cells are arranged in a welldefined, periodic pattern—the cone mosaic—that shows strong heterotypic as well as homotypic correlations [11,12]. The cone mosaic represents a rare vertebrate example of the precise regulation of cell fate and organization at the single cell level (more instances of which have been described in invertebrate systems [13,14])
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