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The mature mammalian kidney arises through a series of reciprocal inductive interactions between two different cell groups, the ureteric bud epithelium and the metanephric mesenchyme. The RET receptor tyrosine kinase is required for induction and development of the metanephric kidney. Differential splicing at the 3' end of RET results in transcripts encoding three isoforms that differ with respect to their C-terminal 9 (RET9), 51 (RET51) or 43 (RET43) amino acids. In vitro assays have identified differences in the abilities of the RET9 and RET51 isoforms to induce differentiation suggesting functional differences between these proteins. We examined the relative expression levels of the three RET 3' splicing variants in developing human kidney using semi-quantitative RT-PCR. We observed consistent expression of the RET9 and RET43 variants in kidney samples spanning 7.5 through 24 weeks gestation. At early gestational ages (7.5-8.5 weeks), RET51 expression was very low (+/-5%) compared to RET9; however, a rapid seven fold increase in expression was detected by 9 weeks. Our data suggest that RET51 may contribute to differentiation-related events occurring after 8.5 weeks gestation rather than to induction of the human kidney.

A series of inductive events between two different cell groups, the ureteric bud epithelium and metanephric mesenchyme, gives rise to the functional mammalian kidney. These reciprocal inductive interactions involve a number of molecules, one of which is the RET receptor tyrosine kinase. The phenotype of mice lacking functional RET includes kidney agenesis or severe dysgenesis, indicating a requirement for RET in kidney organogenesis. To investigate RET expression in human kidney development, we used a semi-quantitative RT-PCR-based strategy to examine a panel of kidney RNA samples ranging from 8-24 weeks gestational age. We found RET expression was highest earlier in development (14 weeks) with expression decreasing through to 24 weeks gestation. While three alternative RET transcripts generated by exon skipping at the 5' end of the gene were all detected throughout kidney development, expression of one transcript, RET2/6, where exon 2 was spliced to exon 6, varied relative to full length RET during this period. Levels of RET2/6 were highest at the earliest age of fetal kidney examined (8 weeks) and decreased relative to all other RET transcripts to low adult levels. The period of high expression coincides with a period of rapid bud bifurcation. Thus, it is possible that RET2/6 has a role in the early growth and differentiation of the human kidney.