Inter-dependent Tissue Growth and Turing Patterning in a Model for Long Bone Development

摘要

The development of long bones requires a sophisticated spatial organizationof cellular signaling, proliferation, and differentiation programs. How suchspatial organization emerges on the growing long bone domain is stillunresolved. Based on the reported biochemical interactions we developed aregulatory model for the core signaling factors IHH, PTCH1, and PTHrP andincluded two cell types, proliferating/resting chondrocytes and(pre-)hypertrophic chondrocytes. We show that the reported IHH-PTCH1interaction gives rise to a Schnakenberg-type Turing kinetics, and thatinclusion of PTHrP is important to achieve robust patterning when couplingpatterning and tissue dynamics. The model reproduces relevant spatiotemporalgene expression patterns, as well as a number of relevant mutant phenotypes. Insummary, we propose that a ligand-receptor based Turing mechanism may controlthe emergence of patterns during long bone development, with PTHrP as animportant mediator to confer patterning robustness when the sensitive Turingsystem is coupled to the dynamics of a growing and differentiating tissue. Wehave previously shown that ligand-receptor based Turing mechanisms can alsoresult from BMP-receptor and GDNF-receptor interactions, and that thesereproduce the wildtype and mutant patterns during digit formation in limbs andbranching morphogenesis in lung and kidneys. Receptor-ligand interactions maythus constitute a general mechanism to generate Turing patterns in nature.