Hisao Honda

Planar Cell Polarity Links Axes of Spatial Dynamics in Neural-Tube Closure

Neural-tube closure is a critical step of embryogenesis, and its failure causes serious birth defects. Coordination of two morphogenetic processes--convergent extension and neural-plate apical constriction--ensures the complete closure of the neural tube. We now provide evidence that planar cell polarity (PCP) signaling directly links these two processes. In the bending neural plates, we find that a PCP-regulating cadherin, Celsr1, is concentrated in adherens junctions (AJs) oriented toward the mediolateral axes of the plates. At these AJs, Celsr1 cooperates with Dishevelled, DAAM1, and the PDZ-RhoGEF to upregulate Rho kinase, causing their actomyosin-dependent contraction in a planar-polarized manner. This planar-polarized contraction promotes simultaneous apical constriction and midline convergence of neuroepithelial cells. Together our findings demonstrate that PCP signals confer anisotropic contractility on the AJs, producing cellular forces that promote the polarized bending of the neural plate.

Description of cellular patterns by Dirichlet domains: The two-dimensional case

Abstract An attempt was made to describe cellular patterns by Dirichlet domains, that are convex polygons which cover a plane without leaving any gaps or overlaps and can be simply determined by a small number of parameters. In order to examine the accuracy of the description, the deviation value was defined. Dirichlet domains were shown to describe some cellular patterns (cultured monolayer cells, epithelial cells in tissue, etc.) with relatively small deviation values. Dirichlet domains were also used for simulation of an experiment in which contiguous cells migrated to fill a space after removal of a single cell in an epithelial sheet.

A dynamic cell model for the formation of epithelial tissues

Abstract A dynamic model is proposed for monolayered epithelial tissue, in which the monolayer is assumed to consist of prismatic cells, so that the system is described as a two-dimensional polygonal pattern. Its dynamic behaviour is determined by equations of motion for vertices in the polygonal pattern and elementary change in the system (change in the connection of vertex pairs). The vertices are driven by the sum of interfacial tension on cell boundaries and the resistance force against the deformation of cells. It is shown by computer simulations that our model possesses the characteristics of epithelial tissue, that is it has a mechanism which makes the edge number and size of a cell uniform and the shape symmetric. This mechanism finally gives rise to a regular polygonal pattern similar to a honeycomb pattern, even though initial patterns have large variations. Local equilibrium dynamics under which the size of each cell is flexibly adapted to its local environment are compared with non-local equilibrium dynamics. The local equilibrium dynamics produce more natural cellular patterns.

Computer simulation of emerging asymmetry in the mouse blastocyst

The mechanism of embryonic polarity establishment in mammals has long been controversial. Whereas some claim prepatterning in the egg, we recently presented evidence that mouse embryonic polarity is not established until blastocyst and proposed the mechanical constraint model. Here we apply computer simulation to clarify the minimal cellular properties required for this morphology. The simulation is based on three assumptions: (1) behavior of cell aggregates is simulated by a 3D vertex dynamics model; (2) all cells have equivalent mechanical properties; (3) an inner cavity with equivalent surface properties is gradually enlarged. However, an initial attempt reveals a requirement for an additional assumption: (4) the surface of the cavity is firmer than intercellular surfaces, suggesting the presence of a basement membrane lining the blastocyst cavity, which is indeed confirmed by published data. The simulation thus successfully produces a structure recapitulating the mouse blastocyst. The axis of the blastocyst, however, remains variable, leading us to an additional assumption: (5) the aggregate is enclosed by a capsule, equivalent to the zona pellucida in vivo. Whereas a spherical capsule does not stabilize the blastocyst axis, an ellipsoidal capsule eventually orients the axis in accordance with its longest diameter. These predictions are experimentally verified by time-lapse recordings of mouse embryos. During simulation, equivalent cells form two distinct populations composed of smaller inner cells and larger outer cells. These results reveal a unique feature of early mammalian development: an asymmetry may emerge autonomously in an equivalent population with no need for a priori intrinsic differences.

How much does the cell boundary contract in a monolayered cell sheet

The method is developed to know how much the cell boundary contracts in a pattern consisting of convex polygonal cells with no gaps nor overlaps; when a cellular pattern is given, we can make it into another pattern whose total boundary length becomes shorter than the original, without reducing the area of each cell. By repetition of such procedure, (1) it can predict the hypothetical cellular pattern whose boundary length has approximated to the shortest possible and, (2) it can estimate the s value, which indicates the degree of lack of boundary shortening of the cellular pattern. The method is applied to several cellular and artificial patterns; cultured epithelial cells in monolayers from lung and pigment retina, epidermis of plant leaf, two-dimensional arrangement of soap bubbles, etc. The results are discussed in relation to recent knowledge on contractile microfilaments in organized cells.

Two different mechanisms of planar cell intercalation leading to tissue elongation.

During development, certain cells intercalate with each other towards tissue‐elongation, exemplified in sea‐urchin gut‐elongation, amphibian gastrulation, and Drosophila germ‐band extension. Their mechanism is not universal among intercalation events. To clarify the minimal cellular properties required for cell‐intercalation, we computer‐simulated the process using three‐dimensional geometrical cell‐models. We identified two different mechanisms: (1) cell‐junction‐remodeling by cell‐junction contraction along a specific direction, as observed in Drosophila germ‐band extension, and (2) cell‐shuffling by orientated cell‐extension of bipolar cells, as observed in amphibian gastrulation. The cell‐junction‐remodeling was characterized by well‐defined accumulation of contractile molecules along a specific direction of cell‐junctions. Length contraction of approximately one cell‐junction per cell is enough for the entire tissue‐elongation. The cell‐shuffling was characterised by rhythmic cell‐extension and orientated movement of cytoskeleton within the elongated cells. Furthermore, tissue‐elongation along a polarized axis was limited to a 2.5‐fold increase in the cell‐junction‐remodeling, while no limit was defined for the cell‐shuffling. Developmental Dynamics 237:1826–1836, 2008.

Epidermal remodelling in psoriasis

Psoriatic hyperproliferative epidermis is characterized by a regular elongation of rete ridges, accompanied by altered keratinization. Another notable finding is close positioning of the vasculature to the suprapapillary epidermis. These architectural/morphological changes are naturally described by a concept of epidermal remodelling based on decreased epidermal turnover time. The recently described positioning of stem cells to the tips of dermal papillae fits nicely with this concept.

Formation of the branching pattern of blood vessels in the wall of the avian yolk sac studied by a computer simulation

The present study was performed to provide data to support the notion previously believed but not proved experimentally or theoretically, that blood vessels are formed by the selection of capillaries in the network. In an attempt to understand the mechanism of formation of blood vessel branching structures, the transformation of a capillary network to a branching system in the wall of quail yolk sac was successively recorded by a series of photographs, and a computer simulation was carried out for the process of in vivo vascularization based on the photographs. The simulation demonstrated that a positive feedback system participated in the formation of a branching structure. That is, vessels which had been much used were enlarged, whereas less used vessels were reduced in their size and finally extinguished. The enlarged vessels became major components of the branching system. As the body of an embryo grew, it was observed that polygonal capillary networks enlarged, which led each polygon of the network to divide into a few finer polygons. Then, some of the capillary vessels were again selected and formed a branching system. This process repeated during the body growth, indicating that the vascular system developed adaptively to the body growth. A region where the growth was fast, received much blood flow and produced finer networks of capillaries. Thus, it was experimentally demonstrated for the first time that capillaries in the network are successively selected by a positive feedback mechanism and form blood vessels.

Establishment of epidermal cell columns in mammalian skin: Computer simulation

Abstract The present investigation shows an example of tissue formation in relation to individual cell properties. Epidermis of mammalian skin has recently been shown to be organized during ontogeny into neat vertical cell columns, in which a cell approximates the flattened form of Kelvins tetrakaidecahedron, a 14-sided body with eight hexagonal faces and six square faces. Such an epidermal architecture is compatible with the organization and turnover of stacked cells, a constant loss of surface cells and a supply that cells from a basal layer differentiate during migration to the surface. The developmental process from irregular cell aggregate into neat columns in skin is simulated on a digital electronic computer with the assumption as follows: a new cell migrating upward from a basal layer jostles and settles at the less crowded area among upper cells. After migration of many cells to the surface, the simulation demonstrates that cells have been stacked in neat columns, and the stability of the architecture is also shown.

Differentiation of wing epidermal scale cells in a butterfly under the lateral inhibition model--appearance of large cells in a polygonal pattern.

Cellular pattern formations of some epithelia are believed to be governed by the direct lateral inhibition rule of cell differentiation. That is, initially equivalent cells are all competent to differentiate, but once a cell has differentiated, the cell inhibits its immediate neighbors from following this pathway. Such a differentiation repeats until all non-inhibited cells have differentiated. The cellular polygonal patterns can be characterized by the numbers of undifferentiated cells and differentiated ones. When the differentiated cells become large in size, the polygonal pattern is deformed since more cells are needed to enclose the large cell. An actual example of such a cellular pattern was examined. The pupal wing epidermis of a butterfly Pieris rapae shows a transition of the equivalent-size cell pattern to the pattern involving large cells. The process of the transition was analyzed by using the method of weighted Voronoi tessellation that is useful for treatment of irregularly sized polygons. The analysis supported that the pattern transition of the early stage of the pupal wing epidermis is governed by the lateral inhibition rule. The differentiation takes place in order of largeness, but not smallness, of the apical polygonal area in the differentiating region of the pupal wing.