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

Nat Commun. 2019 Jan 16;10(1):239. doi: 10.1038/s41467-018-08212-8.

Abstract

Branching patterns and regulatory networks differ between branched organs. It has remained unclear whether a common regulatory mechanism exists and how organ-specific patterns can emerge. Of all previously proposed signalling-based mechanisms, only a ligand-receptor-based Turing mechanism based on FGF10 and SHH quantitatively recapitulates the lung branching patterns. We now show that a GDNF-dependent ligand-receptor-based Turing mechanism quantitatively recapitulates branching of cultured wildtype and mutant ureteric buds, and achieves similar branching patterns when directing domain outgrowth in silico. We further predict and confirm experimentally that the kidney-specific positive feedback between WNT11 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 and kidneys, 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Animals
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / genetics
  • Computer Simulation
  • Embryo, Mammalian
  • Feedback, Physiological
  • Female
  • Glial Cell Line-Derived Neurotrophic Factor / metabolism*
  • Image Processing, Computer-Assisted
  • Kidney / diagnostic imaging
  • Kidney / growth & development*
  • Luminescent Proteins / chemistry
  • Luminescent Proteins / genetics
  • Mice
  • Mice, Transgenic
  • Microscopy, Fluorescence / methods
  • Models, Biological*
  • Organ Culture Techniques
  • Organogenesis*
  • Proto-Oncogene Proteins c-ret / metabolism*
  • Signal Transduction / physiology
  • Time-Lapse Imaging / methods
  • Tomography, Optical / methods
  • Wnt Proteins / metabolism*

Substances

  • Bacterial Proteins
  • Gdnf protein, mouse
  • Glial Cell Line-Derived Neurotrophic Factor
  • Luminescent Proteins
  • Wnt Proteins
  • Wnt11 protein, mouse
  • yellow fluorescent protein, Bacteria
  • Proto-Oncogene Proteins c-ret
  • Ret protein, mouse