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

Theory of branching morphogenesis by local interactions and global guidance

Branching morphogenesis governs the formation of many organs such as lung, kidney, and the neurovascular system. Many studies have explored system-specific molecular and cellular regulatory mechanisms, as well as self-organizing rules underlying branching morphogenesis. However, in addition to local cues, branched tissue growth can also be influenced by global guidance. Here, we develop a theoretical framework for a stochastic self-organized branching process in the presence of external cues. Combining analytical theory with numerical simulations, we predict differential signatures of global vs. local regulatory mechanisms on the branching pattern, such as angle distributions, domain size, and space-filling efficiency. We find that branch alignment follows a generic scaling law determined by the strength of global guidance, while local interactions influence the tissue density but not its overall territory. Finally, using zebrafish innervation as a model system, we test these key features of the model experimentally. Our work thus provides quantitative predictions to disentangle the role of different types of cues in shaping branched structures across scales

mTOR signalling, embryogenesis and the control of lung development

The existence of a nutrient sensitive “autocatakinetic” regulator of embryonic tissue growth has been hypothesised since the early 20th century, beginning with pioneering work on the determinants of foetal size by the Australian physiologist, Thorburn Brailsford-Robertson. We now know that the mammalian target of rapamycin complexes (mTORC1 and 2) perform this essential function in all eukaryotic tissues by balancing nutrient and energy supply during the first stages of embryonic cleavage, the formation of embryonic stem cell layers and niches, the highly specified programmes of tissue growth during organogenesis and, at birth, paving the way for the first few breaths of life. This review provides a synopsis of the role of the mTOR complexes in each of these events, culminating in an analysis of lung branching morphogenesis as a way of demonstrating the central role mTOR in defining organ structural complexity. We conclude that the mTOR complexes satisfy the key requirements of a nutrient sensitive growth controller and can therefore be considered as Brailsford-Robertson's autocatakinetic centre that drives tissue growth programmes during foetal development

Multiscale dynamics of branching morphogenesis.

Branching morphogenesis is a prototypical example of complex three-dimensional organ sculpting, required in multiple developmental settings to maximize the area of exchange surfaces. It requires, in particular, the coordinated growth of different cell types together with complex patterning to lead to robust macroscopic outputs. In recent years, novel multiscale quantitative biology approaches, together with biophysical modelling, have begun to shed new light of this topic. Here, we wish to review some of these recent developments, highlighting the generic design principles that can be abstracted across different branched organs, as well as the implications for the broader fields of stem cell, developmental and systems biology.wellcome trust royal societ

Fractal analysis of vascular networks : insights from morphogenesis

Considering their extremely complicated and hierarchical structure, a long standing question in vascular physio-pathology is how to characterize blood vessels patterns, including which parameters to use. Another question is how to define a pertinent taxonomy, with applications to normal development and to diagnosis and/or staging of diseases. To address these issues, fractal analysis has been applied by previous investigators to a large variety of healthy or pathologic vascular networks whose fractal dimensions have been sought. A review of the results obtained on healthy vascular networks first shows that no consensus has emerged about whether normal networks must be considered as fractals or not. Based on a review of previous theoretical work on vascular morphogenesis, we argue that these divergences are the signature of a two-step morphogenesis process, where vascular networks form via progressive penetration of arterial and venous quasi-fractal arborescences into a pre-existing homogeneous capillary mesh. Adopting this perspective, we study the multi-scale behavior of generic patterns (model structures constructed as the superposition of homogeneous meshes and quasi-fractal trees) and of healthy intracortical networks in order to determine the artifactual and true components of their multi-scale behavior. We demonstrate that, at least in the brain, healthy vascular structures are a superposition of two components: at low scale, a mesh-like capillary component which becomes homogeneous and space-filling over a cut-off length of order of its characteristic length; at larger scale, quasi-fractal branched (tree-like) structures. Such complex structures are consistent with all previous studies on the multi-scale behavior of vascular structures at different scales, resolving the apparent contradiction about their fractal nature. Consequences regarding the way fractal analysis of vascular networks should be conducted to provide meaningful results are presented. Finally, consequences for vascular morphogenesis or hemodynamics are discussed, as well as implications in case of pathological conditions, such as cancer