Loss of Sprouty2 partially rescues renal hypoplasia and stomach hypoganglionosis but not intestinal aganglionosis in Ret Y1062F mutant mice

Abstract

The glial cell line-derived neurotrophic factor (GDNF)/RET tyrosine kinase signaling pathway plays crucial roles in the development of the enteric nervous system (ENS) and the kidney. Tyrosine 1062 (Y1062) in RET is an autophosphorylation residue that is responsible for the activation of the PI3K/AKT and RAS/MAPK signaling pathways. Mice lacking signaling via Ret Y1062 show renal hypoplasia and hypoganglionosis of the ENS although the phenotype is milder than the Gdnf- or Ret-deficient mice. Sprouty2 (Spry2) was found to be an antagonist for fibroblast growth factor receptor (FGFR) and acts as an inhibitory regulator of ERK activation. Spry2-deficient mice exhibit hearing loss and enteric nerve hyperplasia. In the present study, we generated Spry2-deficient and Ret Y1062F knock-in (tyrosine 1062 is replaced with phenylalanine) double mutant mice to see if abnormalities of the ENS and kidney, caused by loss of signaling via Ret Y1062, are rescued by a deficiency of Spry2. Double mutant mice showed significant recovery of ureteric bud branching and ENS development in the stomach. These results indicate that Spry2 regulates downstream signaling mediated by GDNF/RET signaling complex in vivo.

https://researchopenworld.com/analysis-of-copy-number-variations-and-knockdown-in-zebrafish-pronephros-identifies-novel-candidate-cakut-genes/#

“…Defective growth and branching of the nephric duct and ureteric bud are characteristic of mutations in the c-Ret receptor tyrosine kinase, which is essential for normal development of the mammalian kidney and lower urinary tract [17]. Spry2 plays a critical role in regulating c-Ret in developing kidney [18,19]. Spred1 encoding for the Sprouty1-related gene product is a negative regulator of Ras-Mitogen Activated Protein Kinase (MAPK) activity.…”

Identification of a Key Motif That Determines the Differential Surface Levels of RET and TrkB Tyrosine Kinase Receptors and Controls Depolarization Enhanced RET Surface Insertion

“…For example, phosphorylated Tyr 1062 has the capacity to recruit PI3K/Akt, Ras/Erk, and so on for downstream transduction (38,39). GDNF-stimulated phosphorylation of Erk and Akt in DRG neurons is significantly decreased in Y1062F homozygous mice, which die within 1 month after birth due to serious developmental deficiencies during embryogenesis (40,41). In addition to the tyrosines, the RET Ser 696 residue, which acts as PKA phosphorylation site, is required for GDNF-mediated activation of the Rac signaling pathway (27).…”

Sprouty2 expression controls endothelial monolayer integrity and quiescence

“…In subsequent study the authors showed that increased FGF signaling resulted in decreased apoptosis and increased proliferation [155]. Finally, loss of Sprouty2 partially rescues renal hypoplasia and stomach hypoganlionosis in Ret Y1062F mutant mice by regulating downstream signaling of the GDNF/RET complex [156].…”