A human yeast artificial chromosome containing the multiple endocrine neoplasia type 2B Ret mutation does not induce medullary thyroid carcinoma but does support the growth of kidneys and partially rescues enteric nervous system development in Ret-deficient mice.
We generated a line of transgenic mice using a yeast artificial chromosome containing the Ret mutation responsible for the multiple endocrine neoplasia type 2B syndrome (MEN 2B). The resulting animals did not develop any of the expected neoplasms associated with MEN 2B. Transgenic animals were then bred with animals lacking murine Ret (Ret(M)) to further evaluate the function of human mutated Ret (Ret(H)(2B)) in the murine context. Whereas mice lacking Ret(M) exhibit intestinal aganglionosis and the absence of kidneys with other genitourinary anomalies, expression of the Ret(H)(2B) transgene in Ret(M)-deficient mice allowed significant renal development with a partial rescue of the enteric nervous system. These Ret(H)(2B)-positive/Ret(M)-deficient mice exhibit normal Ret expression and survive longer than Ret(M)-deficient mice, but still die at 3 to 5 days of age with evidence of enterocolitis. We conclude that the normal expression of a human Ret proto-oncogene with the MEN 2B mutation does not cause any features of MEN 2B in mice. Although the gene is normally expressed in the appropriate target tissues, there is incomplete phenotypic rescue in mice lacking murine Ret. These results suggest important interspecies differences between humans and mice in the function of the Ret oncogene.
Skinner
Michael A
MA
Department of Surgery, Duke University Medical Center, Box 3815, Durham, NC 27710, USA. skinn009@mc.duke.edu
Kalyanaraman
Somasundaram
S
Safford
Shawn D
SD
Heuckeroth
Robert O
RO
Tourtellotte
Warren
W
Goyeau
Dominique
D
Goodfellow
Paul
P
Milbrandt
Jeffrey D
JD
Freemerman
Alex
A
D000818:Animals; D001483:Base Sequence; D018244:Chromosomes, Artificial, Yeast / Q000502:physiology*; D017931:DNA Primers; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018814:Multiple Endocrine Neoplasia Type 2b / Q000235:genetics* / Q000517:prevention & control; D016133:Polymerase Chain Reaction; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000172:deficiency* / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000172:deficiency* / Q000235:genetics*; D015183:Restriction Mapping
D017931:DNA Primers; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C494999:Ret protein, mouse