Loss of Sprouty2 partially rescues renal hypoplasia and stomach hypoganglionosis but not intestinal aganglionosis in Ret Y1062F mutant mice.
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.
Department of Pathology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
Rieko
R
Miyamoto
Mayumi
M
Jijiwa
Masato
M
Asai
Kumi
K
Kawai
Maki
M
Ishida-Takagishi
Shinji
S
Mii
Naoya
N
Asai
Atsushi
A
Enomoto
Yoshiki
Y
Murakumo
Akihiko
A
Yoshimura
Masahide
M
Takahashi
D048868:Adaptor Proteins, Signal Transducing; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D017931:DNA Primers / Q000235:genetics; D004065:Digestive System Abnormalities / Q000235:genetics* / Q000378:metabolism; D017615:Enteric Nervous System / Q000473:pathology; D055879:Gene Knock-In Techniques; D005838:Genotype; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism*; D006652:Histological Techniques; D006965:Hyperplasia / Q000209:etiology / Q000473:pathology; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D007668:Kidney / Q000002:abnormalities* / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000172:deficiency*; D051379:Mice; D008817:Mice, Mutant Strains; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism*; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D017931:DNA Primers; D051100:Glial Cell Line-Derived Neurotrophic Factor; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D017468:Receptors, Fibroblast Growth Factor; D051096:Proto-Oncogene Proteins c-ret; C494999:Ret protein, mouse; D017346:Protein Serine-Threonine Kinases; C118389:Spry2 protein, mouse