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THE WILMS' TUMOR Suppressor Gene-1 (WT1) Encodes a Zinc Finger

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THE WILMS' TUMOR Suppressor Gene-1 (WT1) Encodes a Zinc Finger 128 RESEARCH NEWS Kidneys and Sex, the Wilms’ Tumor Connection A review of: Hammes A, Guo JK, Lutsch JR et al. 2001 Two splice variants of the Wilms’ tumor 1 gene have distinct functions during sex determination and nephron formation. Cell 106: 319–329 HE WILMS’ TUMOR suppressor gene-1 erally suggested to be involved in post- JORDAN KREIDBERG T(WT1) encodes a zinc finger pro- transcriptional events, yet the molecu- tein involved in gene regulation during are equivalent; an issue that could not lar data pertaining to male-specific kidney, gonad, and heart development. adequately be dealt with in this study.) targets is more consistent with a role Targeted mutation of the Wt1 gene in The phenotype of the ϩKTS-only mu- for WT1 as a transcriptional regulator. mice led to a failure of kidney and tation is more severe. Small kidneys There may well be some degree of gonadal development (1). WT1 is al- with poorly formed glomeruli are overlap in the functions of the different ternatively spliced, with one alterna- present, and gonads are also very WT1 isoforms. Further studies that tive splicing event resulting in the in- poorly developed. In contrast, the phe- unify molecular data with genetic and clusion of three amino acids, lysine- notype of the Frasier mice bore strong developmental results will continue to threonine-serine (KTS) at the end of resemblance to the human FS. Hetero- unravel these mysteries of WT1. the third zinc finger, an insertion that zygote Frasier mice developed glomer- affects the DNA binding and subcellu- ulosclerosis, and homozygotes also 1. Kreidberg J.A., Sariola H, Loring JM, Maeda M, lar localization of the WT1 protein. Pelletier J, Housman D, Jaenisch R 1997 WT-1 is had poorly developed glomeruli, required for early kidney development. Cell 74:679– Frasier syndrome, which includes go- though not as severely dysgenic as 691 nadal dysgenesis and glomerulosclero- ϩ 2. Barbaux S, Niaudet P, Gubler MC, Grunfeld JP, KTS homozygotes. Frasier heterozy- Jaubert F, Kuttenn F, Fekete CN, Souleyreau- sis (but strangely no Wilms’ tumors), gous mice will therefore provide a use- Therville N, Thibaud E, Fellous M, McElreavey K is due to specific dominant mutations 1997 Donor splice-site mutations in WT1 are re- ful model system for understanding the sponsible for Frasier syndrome. Nat Genet 17:467– in the Wt1 gene that result in an inabil- changes in gene expression that lead to 470 ity to splice in the KTS sequence, thus glomerulosclerosis. Most remarkably, 3. Kikuchi H, Takata A, Akasaka Y, Fukuzawa R, ϩ Yoneyama H, Kurosawa Y, Honda M, Kamiyama Y, reducing the dosage of the KTS iso- gonads in embryonic male Frasier ho- Hata J 1998 Do intronic mutations affecting splicing forms (2, 3). This observation implied of WT1 exon 9 cause Frasier syndrome? J Med mozygotes had the morphological ap- Genet 35:45–48 that there were indeed distinct roles for pearance of ovaries, with deficient go- 4. Hammes A., Guo JK, Lutsch G, Leheste JR, Land- individual WT1 isoforms in urogenital rock D, Ziegler U, Gubler MC, Schedl A 2001 Two nadal expression of Sry and Sox9. splice variants of the Wilms’ tumor 1 gene have development. A greater understanding Thus the study of Hammes et al pro- distinct functions during sex determination and of these distinct roles was recently pro- nephron formation. Cell 106:319–329 vides support to earlier molecular stud- 5. Hossain A, Saunders GF 2001 The human sex- vided by Hammes et al from the labo- ies (5–7). by establishing a genetic role determining gene SRY is a direct target of WT1. ratory of Andreas Schedl. They pub- J Biol Chem 276:16817–16823 for WT1 in regulating Sry, Dax1 and 6. Kim J, Prawitt D, Bardeesy N, Torban E, Vicaner C, lished an elegant study in Cell in which MIS expression, and by certifying Wt1 Goodyer P, Zabeland B, Pelletier J 1999 The Wilms’ targeted mutagenesis was used to de- tumor suppressor gene (wt1) product regulates as a key player in male gonadal devel- Dax-1 gene expression during gonadal differentia- rive mice that could either only express opment. So, the ϩKTS form of WT1 tion Mol Cell Biol 19:2289–2299 the ϩKTS version of WT1, or the 7. Nachtigal MW, Hirokawa Y, Enyeart-VanHouten may be specifically involved in regu- DL, Flanagan JN, Hammerand GD, Ingraham HA non-KTS (dubbed the Frasier allele) lating male pathways. However, from 1998 Wilms’ tumor 1 and Dax-1 modulate the or- version, but not both (4). The pheno- phan nuclear receptor SF-1 in sex-specific gene ex- this interpretation there arise additional pression. Cell 93:445–454 types of these mice are different, dem- enigmatic questions: if the ϩKTS form onstrating that with regard the KTS is specifically involved in male go- sequence, there are indeed distinct nadal development, how did early in- Division of Nephrology Children’s Hospital roles for the different splice forms. different gonad development proceed 300 Longwood Avenue (This interpretation assumes that WT1 in the absence of the ϪKTS form? Boston, MA 02115 protein levels from the two mutations Additionally, the ϩKTS form is gen- U.S.A..
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