Tilmann Glimm

Dynamical mechanisms for skeletal pattern formation in the vertebrate limb

We describe a ‘reactor–diffusion’ mechanism for precartilage condensation based on recent experiments on chondrogenesis in the early vertebrate limb and additional hypotheses. Cellular differentiation of mesenchymal cells into subtypes with different fibroblast growth factor (FGF) receptors occurs in the presence of spatio–temporal variations of FGFs and transforming growth factor–betas (TGF–βs). One class of differentiated cells produces elevated quantities of the extracellular matrix protein fibronectin, which initiates adhesion–mediated preskeletal mesenchymal condensation. The same class of cells also produces an FGF–dependent laterally acting inhibitor that keeps condensations from expanding beyond a critical size. We show that this ‘reactor–diffusion’ mechanism leads naturally to patterning consistent with skeletal form, and describe simulations of spatio–temporal distribution of these differentiated cell types and the TGF–β and inhibitor concentrations in the developing limb bud.

A Framework for Three-Dimensional Simulation of Morphogenesis

We present COMPUCELL3D, a software framework for three-dimensional simulation of morphogenesis in different organisms. COMPUCELL3D employs biologically relevant models for cell clustering, growth, and interaction with chemical fields. COMPUCELL3D uses design patterns for speed, efficient memory management, extensibility, and flexibility to allow an almost unlimited variety of simulations. We have verified COMPUCELL3D by building a model of growth and skeletal pattern formation in the avian (chicken) limb bud. Binaries and source code are available, along with documentation and input files for sample simulations, at http:// compucell.sourceforge.net.

On multiscale approaches to three-dimensional modelling of morphogenesis

In this paper we present the foundation of a unified, object-oriented, three-dimensional biomodelling environment, which allows us to integrate multiple submodels at scales from subcellular to those of tissues and organs. Our current implementation combines a modified discrete model from statistical mechanics, the Cellular Potts Model, with a continuum reaction–diffusion model and a state automaton with well-defined conditions for cell differentiation transitions to model genetic regulation. This environment allows us to rapidly and compactly create computational models of a class of complex-developmental phenomena. To illustrate model development, we simulate a simplified version of the formation of the skeletal pattern in a growing embryonic vertebrate limb.

Optical Design of Single Reflector Systems and the Monge–Kantorovich Mass Transfer Problem

We consider the problem of designing a reflector that transforms a spherical wave front with a given intensity into an output front illuminating a prespecified region of the far-sphere with prescribed intensity. In earlier approaches, it was shown that in the geometric optics approximation this problem is reduced to solving a second order nonlinear elliptic partial differential equation of Monge–Ampere type. We show that this problem can be solved as a variational problem within the framework of Monge–Kantorovich mass transfer problem. We develop the techniques used by the authors in their work “Optical Design of Two-Reflector Systems, the Monge–Kantorovich Mass Transfer Problem and Fermats Principle” [Preprint, 2003], where the design problem for a system with two reflectors was considered. An important consequence of this approach is that the design problem can be solved numerically by tools of linear programming. A known convergent numerical scheme for this problem was based on the construction of very special approximate solutions to the corresponding Monge–Ampere equation. Bibliography: 14 titles.

Multiscale dynamics of biological cells with chemotactic interactions: from a discrete stochastic model to a continuous description.

The cellular Potts model (CPM) has been used for simulating various biological phenomena such as differential adhesion, fruiting body formation of the slime mold Dictyostelium discoideum, angiogenesis, cancer invasion, chondrogenesis in embryonic vertebrate limbs, and many others. We derive a continuous limit of a discrete one-dimensional CPM with the chemotactic interactions between cells in the form of a Fokker-Planck equation for the evolution of the cell probability density function. This equation is then reduced to the classical macroscopic Keller-Segel model. In particular, all coefficients of the Keller-Segel model are obtained from parameters of the CPM. Theoretical results are verified numerically by comparing Monte Carlo simulations for the CPM with numerics for the Keller-Segel model.

From Genes to Organisms Via the Cell: A Problem-Solving Environment for Multicellular Development

To gain performance, developers often build scientific applications in procedural languages, such as C or Fortran, which unfortunately reduces flexibility. To address this imbalance, the authors present CompuCell3D, a multitiered, flexible, and scalable problem-solving environment for morphogenesis simulations thats written in C++ using object-oriented design patterns.

Stability of n-dimensional patterns in a generalized Turing system: implications for biological pattern formation

The stability of Turing patterns in an n-dimensional cube (0 ,π ) n is studied, where n 2. It is shown by using a generalization of a classical result of Ermentrout concerning spots and stripes in two dimensions that under appropriate assumptions only sheet-like or nodule-like structures can be stable in an n-dimensional cube. Other patterns can also be stable in regions comprising products of lower-dimensional cubes and intervals of appropriate length. Stability results are applied to a new model of skeletal pattern formation in the vertebrate limb.

Reaction–Diffusion Systems and External Morphogen Gradients: The Two-Dimensional Case, with an Application to Skeletal Pattern Formation

We investigate a reaction–diffusion system consisting of an activator and an inhibitor in a two-dimensional domain. There is a morphogen gradient in the domain. The production of the activator depends on the concentration of the morphogen. Mathematically, this leads to reaction–diffusion equations with explicitly space-dependent terms. It is well known that in the absence of an external morphogen, the system can produce either spots or stripes via the Turing bifurcation. We derive first-order expansions for the possible patterns in the presence of an external morphogen and show how both stripes and spots are affected. This work generalizes previous one-dimensional results to two dimensions. Specifically, we consider the quasi-one-dimensional case of a thin rectangular domain and the case of a square domain. We apply the results to a model of skeletal pattern formation in vertebrate limbs. In the framework of reaction–diffusion models, our results suggest a simple explanation for some recent experimental findings in the mouse limb which are much harder to explain in positional-information-type models.

Computational and mathematical models of chondrogenesis in vertebrate limbs

The production of cartilage (chondrogenic patterning) in the limb is one of the best-studied examples of the emergence of form in developmental biology. At the core of the theoretical study is an effort to understand the mechanism that establishes the characteristic distribution of cartilage in the embryonic limb, which defines the future sites and shapes of bones that will be present in the mature limb. This review article gives an overview of the history and current state of a rich literature of mathematical and computational models that seek to contribute to this problem. We describe models for the mechanisms of limb growth and shaping via interaction with various chemical fields, as well as models addressing the intrinsic self-organization capabilities of the embryonic mesenchymal tissue, such as reaction-diffusion and mechanochemical models. We discuss the contributions of these models to the current understanding of chondrogenesis in vertebrate limbs, as well as their relation to the varied conceptual models that have been proposed by experimentalists.

Deep Phylogenomics of a Tandem-repeat Galectin Regulating Appendicular Skeletal Pattern Formation

BackgroundA multiscale network of two galectins Galectin-1 (Gal-1) and Galectin-8 (Gal-8) patterns the avian limb skeleton. Among vertebrates with paired appendages, chondrichthyan fins typically have one or more cartilage plates and many repeating parallel endoskeletal elements, actinopterygian fins have more varied patterns of nodules, bars and plates, while tetrapod limbs exhibit tandem arrays of few, proximodistally increasing numbers of elements. We applied a comparative genomic and protein evolution approach to understand the origin of the galectin patterning network. Having previously observed a phylogenetic constraint on Gal-1 structure across vertebrates, we asked whether evolutionary changes of Gal-8 could have critically contributed to the origin of the tetrapod pattern.ResultsTranslocations, duplications, and losses of Gal-8 genes in Actinopterygii established them in different genomic locations from those that the Sarcopterygii (including the tetrapods) share with chondrichthyans. The sarcopterygian Gal-8 genes acquired a potentially regulatory non-coding motif and underwent purifying selection. The actinopterygian Gal-8 genes, in contrast, did not acquire the non-coding motif and underwent positive selection.ConclusionThese observations interpreted through the lens of a reaction-diffusion-adhesion model based on avian experimental findings can account for the distinct endoskeletal patterns of cartilaginous, ray-finned, and lobe-finned fishes, and the stereotypical limb skeletons of tetrapods.