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A Targeting Mutation of Tyrosine 1062 in Ret Causes a Marked Decrease of Enteric Neurons and Renal Hypoplasia

Mayumi Jijiwa,^1, Toshifumi Fukuda,^1,, Kumi Kawai,² Akari Nakamura,¹ Kei Kurokawa,² Yoshiki Murakumo,¹ Masatoshi Ichihara,¹ and Masahide Takahashi^1,2*

Department of Pathology,¹ Division of Molecular Pathology, Center for Neural Disease and Cancer, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan²

Received 26 November 2003/ Returned for modification 24 January 2004/ Accepted 26 June 2004

The Ret receptor tyrosine kinase plays a crucial role in the development of the enteric nervous system and the kidney. Tyrosine 1062 in Ret represents a binding site for the phosphotyrosine-binding domains of several adaptor and effector proteins that are important for the activation of intracellular signaling pathways, such as the RAS/ERK, phosphatidylinositol 3-kinase/AKT, and Jun-associated N-terminal kinase pathways. To investigate the importance of tyrosine 1062 for organogenesis in vivo, knock-in mice in which tyrosine 1062 in Ret was replaced with phenylalanine were generated. Although homozygous knock-in mice were born normally, they died by day 27 after birth and showed growth retardation. The development of the enteric nervous system was severely impaired in homozygous mutant mice, about 40% of which lacked enteric neurons in the whole intestinal tract, as observed in Ret-deficient mice. The rest of the mutant mice developed enteric neurons in the intestine to various extents, although the size and number of ganglion cells were significantly reduced. Unlike Ret-deficient mice, a small kidney developed in all knock-in mice, accompanying a slight histological change. The reduction of kidney size was due to a decrease of ureteric bud branching during embryogenesis. Thus, these findings demonstrated that the signal via tyrosine 1062 plays an important role in histogenesis of the enteric nervous system and nephrogenesis.

M.J. and T. F. contributed equally to this study.

Present address: Department of Developmental Neurobiology, Institute of Development, Aging and Cancer, Tohoku University, Aoba, Sendai, Japan.

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