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First published online 18 October 2006
doi: 10.1242/dev.02616

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Targeted mutation of serine 697 in the Ret tyrosine kinase causes migration defect of enteric neural crest cells

Naoya Asai^1,2, Toshifumi Fukuda³, Zaiqi Wu², Atsushi Enomoto¹, Vassilis Pachnis⁴, Masahide Takahashi^1,*, and Frank Costantini^2,*

¹ Department of Pathology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
² Department of Genetics and Development, Columbia University, 701 West 168th Street, New York, NY 10032, USA.
³ Laboratory of Molecular Biochemistry, School of Life Science, Tokyo University of Pharmacy and Life Science, Tokyo 192-0392, Japan.
⁴ Division of Molecular Neurobiology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.

Author for correspondence (e-mail: mtakaha{at}med.nagoya-u.ac.jp)

Accepted 6 September 2006

The RET receptor tyrosine kinase plays a critical role in the development of the enteric nervous system (ENS) and the kidney. Upon glial-cell-line-derived neurotrophic factor (GDNF) stimulation, RET can activate a variety of intracellular signals, including the Ras/mitogen-activated protein kinase, phosphatidylinositol 3-kinase (PI3K)/AKT, and RAC1/JUN NH₂-terminal kinase (JNK) pathways. We recently demonstrated that the RAC1/JNK pathway is regulated by serine phosphorylation at the juxtamembrane region of RET in a cAMP-dependent manner. To determine the importance of cAMP-dependent modification of the RET signal in vivo, we generated mutant mice in which serine residue 697, a putative protein kinase A (PKA) phosphorylation site, was replaced with alanine (designated S697A mice). Homozygous S697A mutant mice lacked the ENS in the distal colon, resulting from a migration defect of enteric neural crest cells (ENCCs). In vitro organ culture showed an impaired chemoattractant response of the mutant ENCCs to GDNF. JNK activation by GDNF but not ERK, AKT and SRC activation was markedly reduced in neurons derived from the mutant mice. The JNK inhibitor SP600125 and the PKA inhibitor KT5720 suppressed migration of the ENCCs in cultured guts from wild-type mice to comparable degrees. Thus, these findings indicated that cAMP-dependent modification of RET function regulates the JNK signaling responsible for proper migration of the ENCCs in the developing gut.

Key words: RET tyrosine kinase, GDNF, Enteric nervous system, Protein kinase A, JNK, Mouse

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