Image-based modeling of kidney branching morphogenesis reveals GDNF-RET based Turing-type mechanism and pattern-modulating WNT11 feedback

Abstract

Branching patterns and regulatory networks differ between branched organs. It has remainedunclear whether a common regulatory mechanism exists and how organ-specific patterns canemerge. Of all previously proposed signalling-based mechanisms, only a ligand-receptor-based Turing mechanism based on FGF10 and SHH quantitatively recapitulates the lungbranching patterns. We now show that a GDNF-dependent ligand-receptor-based Turingmechanism quantitatively recapitulates branching of cultured wildtype and mutant uretericbuds, and achieves similar branching patterns when directing domain outgrowth in silico. Wefurther predict and confirm experimentally that the kidney-specific positive feedback betweenWNT11 and GDNF permits the dense packing of ureteric tips. We conclude that the ligand-receptor based Turing mechanism presents a common regulatory mechanism for lungs andkidneys, despite the differences in the molecular implementation. Given its flexibility and robustness, we expect that the ligand-receptor-based Turing mechanism constitutes a likely general mechanism to guide branching morphogenesis and other symmetry breaks during organogenesis.