A new mechanism for spatial pattern formation via lateral and protrusion-mediated lateral signalling

Abstract

Tissue organization and patterning are critical during development when genetically identical cells take on different fates. Lateral signalling plays an important role in this process by helping to generate self-organized spatial patterns in an otherwise uniform collection of cells. Recent data suggest that lateral signalling can be mediated both by junctional contacts between neighbouring cells and via cellular protrusions that allow non-neighbouring cells to interact with one another at a distance. However, it remains unclear precisely how signalling mediated by these distinct types of cell–cell contact can physically contribute to the generation of complex patterns without the assistance of diffusible morphogens or pre-patterns. To explore this question, in this work we develop a model of lateral signalling based on a single receptor/ligand pair as exemplified by Notch and Delta. We show that allowing the signalling kinetics to differ at junctional versus protrusion-mediated contacts, an assumption inspired by recent data which show that the cleavage of Notch in several systems requires both Delta binding and the application of mechanical force, permits individual cells to act to promote both lateral activation and lateral inhibition. Strikingly, under this model, in which Delta can sequester Notch, a variety of patterns resembling those typical of reaction–diffusion systems is observed, together with more unusual patterns that arise when we consider changes in signalling kinetics, and in the length and distribution of protrusions. Importantly, these patterns are self-organizing—so that local interactions drive tissue-scale patterning. Together, these data show that protrusions can, in principle, generate different types of patterns in addition to contributing to long-range signalling and to pattern refinement.

Basal protrusions mediate spatiotemporal patterns of spinal neuron differentiation

“…For example, signaling through long cellular protrusions plays a role during limb patterning in the chick embryo (Sanders et al, 2013), in the development of the zebrafish pigmentation stripes (Eom et al, 2015) as well as neural plate patterning also in the zebrafish (Stanganello et al 2015). In fact, dynamic cellular protrusions from the basal surface of sensory organ precursor (SOP) cells have been proposed to mediate long-distance lateral inhibition to regulate the sparse distribution of mechanosensory bristles in the fly notum and wing disk Cohen et al 2010;Hadjivasiliou et al 2016, 2018. Whether similar protrusive activity mediates long-distance spacing patterns in the vertebrate Central Nervous System (CNS) is not known, but long and short cellular protrusions expressing the Notch ligand Delta-like 1 have been described on intermediate progenitors in the embryonic mammalian cortex (Nelson et al, 2013).…”

Stochastic Simulation of Pattern Formation in Growing Tissue: A Multilevel Approach

“…A small extension to the model was made here in that proliferating cells randomly share Notch and Delta in between each other, thus adding some noise to the overall dynamics. The model itself exhibits a range of intriguing patterns as discussed in [19]. Two such examples are further investigated in…”

“…The time interval was here chosen in a quite conservative way such that a forward Euler step of the original ODE-model (2.2) would imply a 5% change of state in a norm-wise sense, . Parameters are adopted from [19]:…”

“…Zena Hadjivasiliou kindly and patiently detailed several aspects of the running model used throughout this paper [19].…”

“…It has since been realized that cell-to-cell signaling not only is short range, taking place at direct junctional contact sites, but also is mediated via long range cellular protrusions [9]. Mathematical models including these effects have recently been investigated [19,28] and we choose a family of such models as the concrete target in this paper.…”