Differential activities of the RET tyrosine kinase receptor isoforms during mammalian embryogenesis

Esther de Graaff; Shankar Srinivas; Carol Kilkenny; Vivette D'Agati; Baljinder S. Mankoo; Frank Costantini; Vassilis Pachnis

doi:10.1101/gad.205001

Differential activities of the RET tyrosine kinase receptor isoforms during mammalian embryogenesis

¹Division of Developmental Neurobiology, Medical Research Council (MRC) National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK; ²Department of Genetics and Development and ³Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA

Abstract

The RET receptor tyrosine kinase has a critical role in kidney organogenesis and the development of the enteric nervous system. Two major isoforms, RET9 and RET51, differ in the amino acid sequence of the C-terminal tail as a result of alternative splicing. To determine the roles of these isoforms in vivo, we used targeted mutagenesis to generate mice that express either RET9 or RET51. Monoisoformic RET9 mice, which lack RET51, are viable and appear normal. In contrast, monoisoformic RET51 animals, which lack RET9, have kidney hypodysplasia and lack enteric ganglia from the colon. To study the differential activities of the two RET isoforms further, we generated transgenic mice expressing ligand-dependent and constitutively active forms of RET9 or RET51 under the control of the Hoxb7 regulatory sequences. Such RET9 transgenes are capable of rescuing the kidney agenesis in RET-deficient mice or causing kidney hypodysplasia in wild-type animals. In contrast, similar RET51 transgenes fail to rescue the kidney agenesis or cause hypodysplasia. Our findings show that RET9 and RET51 have different signaling properties in vivo and define specific temporal and spatial requirements of c-Ret function during renal development and histogenesis of the enteric nervous system.

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Footnotes

Present addresses: ⁴Department of Clinical Genetics, Erasmus University, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands; ⁵Division of Mammalian Development and ⁶Division of Molecular Neurobiology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK; ⁷Randall Centre for Molecular Mechanisms of Cell Function, GKT School of Biomedical Sciences, New Hunt's House, King's College London, Guy's Campus, London SE1 1UL, UK.
↵8 Corresponding author.
E-MAIL vpachni{at}nimr.mrc.ac.uk; FAX 44-20-89138536.
Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.205001.
- Received April 9, 2001.
- Accepted July 19, 2001.
Cold Spring Harbor Laboratory Press