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doi: 10.1242/10.1242/jcs.00405

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The complex life of WT1

Kay-Dietrich Wagner1, Nicole Wagner1 and Andreas Schedl2,*

1 Johannes-Müller-Institut für Physiologie, Medizinische Fakultät (Charité), Humboldt-Universität Berlin, Germany
2 University of Nice, INSERM U470, 06108 Nice, France



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  		Fig. 1. Model for splice-specific functions of WT1. The mammalian WT1 gene consists of 10 exons. Post-transcriptional modifications result in the generation of 24 isoforms. Exons 5 and 9 are alternatively spliced. Exon 5 encodes 17 additional amino acids; the use of alternative splice donor site 2 of exon 9 results in inclusion of the three amino acids lysine, threonine and serine (+KTS). The ratio between WT1(+KTS) and WT1(-KTS) proteins is nearly constant in all cell types, whereas the ratio of exon 5 splice variants differs. It is speculated that alternative splicing of exon 5 has a modulatory role on WT1 function; the -KTS variant acts as transcriptional regulator; and the +KTS splice variant might have a role in RNA processing. In mouse strains, which specifically lack the WT1(-KTS) or WT1(+KTS) splice variant, the urogenital phenotype is more severe in mice lacking the WT1(-KTS) variant. Animals lacking the WT1(+KTS) variant represent a mouse model for the human Frasier syndrome.

 


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  		Fig. 2. WT1 acts at multiple steps during gonad formation and sex determination. WT1(-KTS) variants can transactivate Sf1. Both WT1 and Sf1 are required for survival of the bi-potential gonads. WT1(+KTS) products are necessary for the expression of high levels of the sex-determining gene Sry. Sry directly or indirectly leads to the activation of Sox9, which in turn stimulates the expression of the anti-Mullerian hormone MIS (AMH). Furthermore, WT1(-KTS) can directly transactivate MIS, Dax1 and at least indirectly Wnt-4. Transactivation of the MIS promoter is achieved through the direct interaction of WT1(-KTS) with SF1 protein. This transactivation of the MIS promoter, but also the Dax1 promoter is increased through interaction of WT1 with the LIM-only co-activator FHL2. Dax1, a gene that can interfere with male sexual development is a repressor of the MIS promoter.

 




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