The prepattern transcription factor <i>Irx3</i> directs nephron segment identity

Reggiani, Luca; Raciti, Daniela; Airik, Rannar; Kispert, Andreas; Brändli, André W.

doi:10.1101/gad.450707

Cited by 105 publications

(177 citation statements)

References 59 publications

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“…The Irx genes can be distinguished from Mkx by the presence of a highly conserved IRO Box in the carboxy-terminal half of all Irx genes (Burglin, 1997). Vertebrate members of the Irx family regulate a diverse set of developmental events, including chamberspecific transcription in the heart, specification and positional identity of the vertebrate neuroectoderm, branching morphogenesis in the lungs, patterning of the nephron, and formation of the zebrafish organizer (Bao et al, 1999;Bruneau et al, 2001;Kudoh and Dawid, 2001;GomezSkarmeta and Modolell, 2002;Matsumoto et al, 2004;Lecaudey et al, 2005;van Tuyl et al, 2006;Reggiani et al, 2007). Studies carried out with chick Irx2 and Drosophila Mirr predict that the Irx family members function to repress transcription (Matsumoto et al, 2004;Bilioni et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

The homeobox gene Mohawk represses transcription by recruiting the sin3A/HDAC co‐repressor complex

Anderson

Beres

Wilson‐Rawls

et al. 2009

Developmental Dynamics

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Section: Introductionmentioning

confidence: 99%

The homeobox gene Mohawk represses transcription by recruiting the sin3A/HDAC co‐repressor complex

Anderson

Beres

Wilson‐Rawls

et al. 2009

Developmental Dynamics

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“…We further demonstrate that the smallest region of overlap for 16q deletions in our material contains the IRXB gene cluster (IRX3, IRX5, and IRX6), of which IRX3 has recently been shown to act as a master regulator of intermediate tubule fate and to be necessary and sufficient to specify nephron segment identity in the developing kidney. 23 Blastemal and anaplastic elements exhibiting loss of 16q failed to express the IRX3 protein, in contrast to epithelial and blastemal elements with intact 16q copies. Tumors with 16q deletion showed a lower overall mRNA expression of IRX3 as well as of the other IRXB genes.…”

mentioning

confidence: 99%

Deletions of 16q in Wilms Tumors Localize to Blastemal-Anaplastic Cells and Are Associated with Reduced Expression of the IRXB Renal Tubulogenesis Gene Cluster

Mengelbier

Karlsson

Lindgren

et al. 2010

The American Journal of Pathology

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Wilms tumor is the most common pediatric renal neoplasm, but few molecular prognostic markers have been identified for this tumor. Somatic deletion in the long arm of chromosome 16 (16q) is known to predict a less favorable outcome in Wilms tumor, but the underlying molecular mechanisms are not known. We show that 16q deletions are typically confined to immature anaplastic-blastic tumor elements, while deletions are absent in maturing tumor components. The smallest region of deletion overlap mapped to a 1.8-Mb segment containing the IRXB gene cluster including IRX3, IRX5, and IRX6, of which IRX3 is a recently identified regulator of tubular maturation during nephrogenesis. Tumors with 16q deletion showed a lower overall mRNA expression of IRXB genes, and 16q-deleted tumor cells failed to express IRX3 while it was expressed in differentiating tubular tumor elements with intact 16q. Consistent with a role for IRX3 in tubular differentiation, gene sets linked to Notch signaling, Rho signaling, and ion channel activity were enriched in tumors with high IRX3 expression, while WTs with low expression were enriched for gene sets linked to cell cycle progression. Wilms tumor accounts for more than 95% of kidney tumors in children. The majority of patients receiving modern multimodal therapy are cured, but 10 to 15% still die of disease.1 Histologically, most WTs mimic the fetal developing kidney in which immature cells of the metanephric mesenchyme differentiate into stromal and epithelial elements, the latter of which ultimately give rise to the nephronic tubules and glomeruli.2 The notion that Wilms tumor originates from pluripotent immature cells is supported by its characteristic triphasic histology, including blastemal, epithelial, and stromal components. The blastema consists of undifferentiated mesenchymal cells, resembling the metanephric mesenchyme, while the epithelial component might show different degrees of differentiation, including primitive tubular and glomeruloid formations. Gene expression studies have provided additional evidence for the hypothesis that Wilms tumor results from a differentiation block in embryonic kidney formation; genes overexpressed in Wilms tumor are also

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“…Studies in Xenopus demonstrated that Iroquois (Irx) 3 is necessary for intermediate tubule formation. 33 Intermediate tubule progenitors give rise to epithelia of LOH in mammals. Generation of conditional Irx3-mutant mice will clarify the role of Irx3 in LOH development in mammals.…”

Section: Do Not Distributementioning

confidence: 99%