Software:

EmbryoMaker and NetworkMaker simulation software v 1.0

EmbryoMaker and NetworkMaker virtual appliance

SpiralMaker simulation software v 1.0


Documentation:

EmbryoMaker v 1.0 User's Manual

NetworkMaker User's Manual


Virtual Appliance README
SpiralMaker v 1.0 User's Manual


Movies (GIF):

Apoptosis

Apoptosis: Certain cells within an epithelium (orange) express a gene that triggers cell death. Those cells gradually shrink until they completely disappear.

ECM secretion

Extracellular matrix (ECM) secretion. A flat epithelium lies over a layer of mesenchymal cells. The epithelial cells in the center express a gene product that promotes ECM secretion on their basal side only. Once ECM material starts being secreted, it ocuppies the space between the epithelium and the mesenchyme, displacing them in opposite directions and thus deforming both the epithelial sheet and the mesenchymal layer.

Differential adhesion

Differential adhesion. A group of mesenshymal cells are loosely distributed in space. All of them express a gene product that promotes the random movement of cell parts (analogous to the extension of cell protrusions). Some of them express a certain type of adhesion molecule (type 1 from now on) that has a high homotypic affinity and a low heterotypic affinity. This means that type 1 molecules adhere more strongly to other type 1 molecules than to other types of adhesion molecules. The other cells express a type 2 adhesion molecule, which has a low homotypic affinity but a strong heterotypic affinity for type 1 molecules. The initial distribution of type 1 cells and type 2 cells is random but, over time, type one cells will contact each other through random movements and will stick together. Since the homotypic affinity of type one molecules is stronger than the heterotypic affinity of type 2 molecules for type 1, those latter molecules will end up forming a cohesive ball of type 1 cells in the center while type 2 cells surround them completely.

Directed growth and division

A small group of epithelial cells (each displayed in a different color) starts growing polarized by a molecular gradient (from left to right of the figure).

Contraction

 Apical contraction. In a flat epithelium, the central cells express a gene product that promotes cytoskeletal contraction on the apical side and expansion on the basal side, becoming wedge-shaped (a.k.a. bottle cells). Those cells generate tensile forces on the apical side and compressive forces on the basal side that promote the curvature of the whole epithelium creating a concavity.

Cell migration

A group of mesenchymal cells (red, orange and yellow) move randomly over a flat epithelium (blue). Epithelial cells express an adhesion molecule at different concentrations, forming a spatial gradient of adhesivity. Mesenchymal cells in turn move preferentially to the regions where adhesivity is higher, thus migrating in a directional fashion.

Figure 7 (section)

Figure 7 (whole, gene expression)

The simulation starts with a blastula-like (spheric) epithelium. One cell in the epithelium expresses transcription factor 1 (TF1) in the initial conditions. TF1 promotes an epithelial to mesenchymal transition (EMT) and thus the single cell expressing that gene detaches from the epithelium and moves randomly in the interior of the blastula. TF1 activates the transcription of TF6, a gene that promotes cell motility, cell proliferation and extracellular matrix secretion. While this EMT is still taking place TF1 also activates the transcription of a growth factor precursor (pGF1) and promotes its transformation into a secretable form (GF1). As a result GF1 is secreted by the mesenchymal cells (all obviously descendants of the original cell that did the EMT) and reaches the nearby epithelial inner surface. All epithelial cells express a receptor for GF1 (R1) at the same level in the initial condistions. As a result GF1 bind its receptor in the epithelial cells that are close enough to the proliferating mesenchymal cells. The receptor-ligand complex (RGF1) activates the transcription of TF2. TF2 activates cell contraction in the outer surface of the epithelium (this is a decrease in the pEQD in these nodes), thus mediating a slight invagination near the zone where mesenchymal cells are (that is close to where the EMT took place). Contraction only happens in the outer side because we do not allow TF2 to diffuse whithin the inner side of the cell. TF2 also activates the transcription of a second growth factor precursor gene product and mediates the transformation of this in the secretable form, a second growth factor (GF2). In this case, GF2 is only secreted in the outer surface of the epithelium, since TF2 is located in the outer side only (and thus the production of the secretable form occurs only there) . GF2 binds to receptor R2 which is expressed in all epithelial cells from the initial conditions. The receptor-ligand complex RGF2 activates the transcription of TF3, which is not allowed to diffuse to the inner side of the cell and activates the mechanical expansion of its outer side (increase in pEQD). Since TF2 strongly inhibits transcription of TF3, this one will be expressed only around the territory of expression of TF2, but without overlap. This means that while contraction in the TF2 territory promotes a concavity in the epithelium, TF3 mediated expansion in the surrounding cell will have the oposite effect, promoting a convex curvature surrounding the TF2 mediated concavity. Also, since TF3 expression relies on GF2 signalling this means that the farther from the TF2 territory (GF2 source) the lower the concentration of TF3, thus creating a gradient of TF3 along the whole epithelium, being highest close to the TF2 territory and lowest at the opposite side. TF3 also promotes cell cycle progression on the epithelium, meaning that cells close to the TF2 territory will divide more rapidly than the ones further from it, but not the ones within the concavity. TF3 also inhibits the transcription of another transcription factor (TF5) that is homogenously expressed in al epithelium. Thus, TF5 forms a gradient opposite to the one formed by TF3, meaning that is lowest near the TF2 territory and highest in the opposite side. TF5 also promotes polarization of cells, meaning that cells will become polarized along the gradient formed by TF5, and promoted cell cycle division. This means that the cells located on the opposite side of the TF2 territory will divide in the direction of the gradient, thus promoting an elongation of the whole embryo in that direction. Close and whithin the invagination this oriented proliferation leads to a deepening of the invagination towards the inside of the embryo

Cell contact lateral inhibition (delta-notch like)

A flat sheet of cells express random low levels of a notch-like receptor and a delta-like membrane tethered ligand. When a receptor molecule in one cell binds to a ligand molecule from another cell, the receptor transmits a signal upregulating the expression of receptor and inhibiting the expression of lignad on its own cell. Also, when a ligand molecule in one cell binds to a receptor molecule from another cell, the ligand transmits a signal upregulating the expression of ligand and inhibiting the expression of receptor on its own cell. This results in a chessboard pattern where cells that express the receptor doesn't express the ligand and viceversa. In the animation cell colors correspond to levels of expression of the receptor molecule (blue for low levels and yellow for high levels).

Initial condition files (input files for EmbryoMaker):

Apoptosis

ECM secretion

Differential adhesion

Directed growth and division

Contraction

Cell migration

Complex Gastrula (Figure 6)

Sea urchin gastrulation

Cell contact lateral inhibition (delta-notch like)


Cell Behavior Ontology (CBO) metamodel files:

Sea Urchin gastrulation model