Glial Cell line-derived neurotrophic factor (GDNF) inducible genes regulate neuronal differentiation and kidney development

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Glial cell line-derived neurotrophic factor (GDNF) and its family ligands regulate the survival and differentiation of various neurons through activation of RET tyrosine kinase. On the other hand, the activation of RET by GDNF is required for normal branching of the ureteric bud epithelium in the developing kidney. We searched for immediate-early GDNF responsive genes by mRNA differential display technique and have isolated fourteen genes. In these GDNF inducible genes, we identified a novel gene (named GZF1) with a BTB/POZ domain and 10 tandemly repeated zinc finger motifs and the SEP1 gene that encodes a DNA strand exchange protein involved in the homologous recombination process of Saccharomyces cerevisiae. As observed for other proteins with the BTB/POZ domain, the GZF1 protein had strong transcriptional repressive activity. Intriguingly, its expression was detected at high levels in branching ureteric buds and collecting ducts of mouse metanephric kidney in which RET was also expressed. Antisense phosphorothioated oligodeoxynucleotides of the GZF1 gene markedly impaired the ureteric bud branching in the metanephric organ culture, suggesting that the induction of GZF1 expression via the GDNF/RET signaling system is required for renal branching morphogenesis. In the case of SEP1, we observed that SEP1 induction showed two peaks at 0.5-2 h and 24-48 h after GDNF stimulation. We also found that a high level of SEP1 expression in neurons of the dorsal root and superior cervical ganglia and motor neurons of the spinal cord of mice in which RET is also expressed. In addition, SEP1 was co-immunoprecipitated with alpha-and beta-tubulins from the lysate of mouse brain. These results thus suggested that SEP1 is a GDNF-inducible and microtubule-associated protein that may play a role in the nervous system.