27 research outputs found
Simulations demonstrate a simple network to be sufficient to control branch point selection, smooth muscle and vasculature formation during lung branching morphogenesis
Proper lung functioning requires not only a correct structure of the
conducting airway tree, but also the simultaneous development of smooth muscles
and vasculature. Lung branching morphogenesis is strongly stereotyped and
involves the recursive use of only three modes of branching. We have previously
shown that the experimentally described interactions between Fibroblast growth
factor (FGF)10, Sonic hedgehog (SHH) and Patched (Ptc) can give rise to a
Turing mechanism that not only reproduces the experimentally observed wildtype
branching pattern but also, in part counterintuitive, patterns in mutant mice.
Here we show that, even though many proteins affect smooth muscle formation and
the expression of Vegfa, an inducer of blood vessel formation, it is sufficient
to add FGF9 to the FGF10/SHH/Ptc module to successfully predict simultaneously
the emergence of smooth muscles in the clefts between growing lung buds, and
Vegfa expression in the distal sub-epithelial mesenchyme. Our model reproduces
the phenotype of both wildtype and relevant mutant mice, as well as the results
of most culture conditions described in the literature.Comment: Initially published at Biology Ope
Digit patterning during limb development as a result of the BMP-receptor interaction
Turing models have been proposed to explain the emergence of digits during
limb development. However, so far the molecular components that would give rise
to Turing patterns are elusive. We have recently shown that a particular type
of receptor-ligand interaction can give rise to Schnakenberg-type Turing
patterns, which reproduce patterning during lung and kidney branching
morphogenesis. Recent knock-out experiments have identified Smad4 as a key
protein in digit patterning. We show here that the BMP-receptor interaction
meets the conditions for a Schnakenberg-type Turing pattern, and that the
resulting model reproduces available wildtype and mutant data on the expression
patterns of BMP, its receptor, and Fgfs in the apical ectodermal ridge (AER)
when solved on a realistic 2D domain that we extracted from limb bud images of
E11.5 mouse embryos. We propose that receptor-ligand-based mechanisms serve as
a molecular basis for the emergence of Turing patterns in many developing
tissues
Branch Mode Selection during Early Lung Development
Many organs of higher organisms, such as the vascular system, lung, kidney,
pancreas, liver and glands, are heavily branched structures. The branching
process during lung development has been studied in great detail and is
remarkably stereotyped. The branched tree is generated by the sequential,
non-random use of three geometrically simple modes of branching (domain
branching, planar and orthogonal bifurcation). While many regulatory components
and local interactions have been defined an integrated understanding of the
regulatory network that controls the branching process is lacking. We have
developed a deterministic, spatio-temporal differential-equation based model of
the core signaling network that governs lung branching morphogenesis. The model
focuses on the two key signaling factors that have been identified in
experiments, fibroblast growth factor (FGF10) and sonic hedgehog (SHH) as well
as the SHH receptor patched (Ptc). We show that the reported biochemical
interactions give rise to a Schnakenberg-type Turing patterning mechanisms that
allows us to reproduce experimental observations in wildtype and mutant mice.
The kinetic parameters as well as the domain shape are based on experimental
data where available. The developed model is robust to small absolute and large
relative changes in the parameter values. At the same time there is a strong
regulatory potential in that the switching between branching modes can be
achieved by targeted changes in the parameter values. We note that the sequence
of different branching events may also be the result of different growth
speeds: fast growth triggers lateral branching while slow growth favours
bifurcations in our model. We conclude that the FGF10-SHH-Ptc1 module is
sufficient to generate pattern that correspond to the observed branching modesComment: Initially published at PLoS Comput Bio
The control of branching morphogenesis
Many organs of higher organisms are heavily branched structures and arise by an apparently similar process of branching morphogenesis. Yet the regulatory components and local interactions that have been identified differ greatly in these organs. It is an open question whether the regulatory processes work according to a common principle and how far physical and geometrical constraints determine the branching process. Here, we review the known regulatory factors and physical constraints in lung, kidney, pancreas, prostate, mammary gland and salivary gland branching morphogenesis, and describe the models that have been formulated to analyse their impacts