Multiple morphogens and rapid elongation promote segmental patterning during development

Abstract

The vertebrate hindbrain is segmented into rhombomeres (r) initially defined by distinct domains of gene expression. Previous studies have shown that noise-induced gene regulation and cell sorting are critical for the sharpening of rhombomere boundaries, which start out rough in the forming neural plate (NP) and sharpen over time. However, the mechanisms controlling simultaneous formation of multiple rhombomeres and accuracy in their sizes are unclear. We have developed a stochastic multiscale cell-based model that explicitly incorporates dynamic morphogenetic changes (i.e. convergent-extension of the NP), multiple morphogens, and gene regulatory networks to investigate the formation of rhombomeres and their corresponding boundaries in the zebrafish hindbrain. During pattern initiation, the short-range signal, fibroblast growth factor (FGF), works together with the longer-range morphogen, retinoic acid (RA), to specify all of these boundaries and maintain accurately sized segments with sharp boundaries. At later stages of patterning, we show a nonlinear change in the shape of rhombomeres with rapid left-right narrowing of the NP followed by slower dynamics. Rapid initial convergence improves boundary sharpness and segment size by regulating cell sorting and cell fate both independently and coordinately. Overall, multiple morphogens and tissue dynamics synergize to regulate the sizes and boundaries of multiple segments during development.

On the origins of developmental robustness: modeling buffering mechanisms against cell-level noise

“…Thus, a cell from a territory A that becomes surrounded by cells from a territory B will receive more B signal than A signal, and would then change its gene expression to match that of territory B. Similar majority rule mechanisms have been proposed to maintain the identity of rhombomeres in the vertebrate hindbrain (Addison et al, 2018;Qiu et al, 2021;Wilkinson, 2018). Our simulations show that this buffering mechanism can indeed decrease the sinuosity of territories (Fig.…”

Morphogen-directed cell fate boundaries: slow passage through bifurcation and the role of folded saddles

“…One could also consider nonlinear cell fate modelling in the presence of more complex or realistic models of pre-patterning via multiple, interacting morphogens, or by the presence of diffusible species that establish gradients of morphogen suppression and enhancement e.g., sFRP/Wnt (Mii and Taira, 2011;Esteve et al, 2011). In particular, successful patterning may involve a combination of a multitude of morphogens that act simultane-ously, which may be transported by different processes, each with their own characteristic timescale (Qiu et al, 2021). Finally, the dynamics of the internal cell state variables could be made more general by considering different bifurcation scenarios that underlie cell fate acquisition.…”

Zebrafish as a Model to Study Retinoic Acid Signaling in Development and Disease

“…This implies that the two tailed gradient of RA is opposed by Cyp26 enzymatic activity at both the far anterior and posterior ends of the developing fish. In work performed by Qiu et al, RA, FGF, and other morphogenic gradients were wonderfully computationally modeled to highlight the precision necessary for essential fates within the developing hindbrain and the associated rhombomeres within zebrafish [ 167 ].…”