FAT4 Fine-Tunes Kidney Development by Regulating RET Signaling

Hongtao Zhang; Mazdak Bagherie-Lachidan; Caroline Badouel; Leonie Enderle; Philippos Peidis; Rod Bremner; Satu Kuure; Sanjay Jain; Helen McNeill

doi:10.1016/j.devcel.2019.02.004

FAT4 Fine-Tunes Kidney Development by Regulating RET Signaling

Dev Cell. 2019 Mar 25;48(6):780-792.e4. doi: 10.1016/j.devcel.2019.02.004. Epub 2019 Mar 7.

Authors

Hongtao Zhang¹, Mazdak Bagherie-Lachidan², Caroline Badouel³, Leonie Enderle¹, Philippos Peidis¹, Rod Bremner⁴, Satu Kuure⁵, Sanjay Jain⁶, Helen McNeill⁷

Affiliations

¹ Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
² Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
³ Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Centre de Biologie du Développement (CBD), Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, 118 Route de Narbonne, Toulouse 31062, France.
⁴ Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Departments of Ophthalmology and Visual Science, and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
⁵ GM-unit at Laboratory Animal Centre, HiLIFE and Medicum, University of Helsinki, Helsinki 00014, Finland.
⁶ Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
⁷ Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: mcneillh@wustl.edu.

Abstract

FAT4 mutations lead to several human diseases that disrupt the normal development of the kidney. However, the underlying mechanism remains elusive. In studying the duplex kidney phenotypes observed upon deletion of Fat4 in mice, we have uncovered an interaction between the atypical cadherin FAT4 and RET, a tyrosine kinase receptor essential for kidney development. Analysis of kidney development in Fat4^-/- kidneys revealed abnormal ureteric budding and excessive RET signaling. Removal of one copy of the RET ligand Gdnf rescues Fat4^-/- kidney development, supporting the proposal that loss of Fat4 hyperactivates RET signaling. Conditional knockout analyses revealed a non-autonomous role for Fat4 in regulating RET signaling. Mechanistically, we found that FAT4 interacts with RET through extracellular cadherin repeats. Importantly, expression of FAT4 perturbs the assembly of the RET-GFRA1-GDNF complex, reducing RET signaling. Thus, FAT4 interacts with RET to fine-tune RET signaling, establishing a juxtacrine mechanism controlling kidney development.

Keywords: CAKUT; FAT4; RET; Van Maldergem syndrome; cadherin; kidney development; non-autonomous.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cadherins / chemistry
Cadherins / deficiency
Cadherins / metabolism*
Gene Deletion
Glial Cell Line-Derived Neurotrophic Factor / metabolism
Glial Cell Line-Derived Neurotrophic Factor Receptors / metabolism
Humans
Intercellular Signaling Peptides and Proteins
Kidney / abnormalities
Kidney / embryology*
Kidney / metabolism*
Mice
Nerve Tissue Proteins / deficiency
Nerve Tissue Proteins / metabolism
Protein Binding
Proto-Oncogene Proteins c-ret / metabolism*
Signal Transduction*
Up-Regulation

Substances

Cadherins
Dchs1 protein, mouse
Fat4 protein, mouse
Fjx1 protein, mouse
Gfra1 protein, mouse
Glial Cell Line-Derived Neurotrophic Factor
Glial Cell Line-Derived Neurotrophic Factor Receptors
Intercellular Signaling Peptides and Proteins
Nerve Tissue Proteins
Proto-Oncogene Proteins c-ret

Grants and funding

R01 DK082531/DK/NIDDK NIH HHS/United States