The Iroquois homeobox proteins IRX3 and IRX5 have distinct roles in Wilms tumour development and human nephrogenesis

Abstract

Wilms tumour is a paediatric malignancy with features of halted kidney development. Here, we demonstrate that the Iroquois homeobox genes IRX3 and IRX5 are essential for mammalian nephrogenesis and govern the differentiation of Wilms tumour. Knock‐out Irx3 − /Irx5 − mice showed a strongly reduced embryonic nephron formation. In human foetal kidney and Wilms tumour, IRX5 expression was already activated in early proliferative blastema, whereas IRX3 protein levels peaked at tubular differentiation. Accordingly, an orthotopic xenograft mouse model of Wilms tumour showed that IRX3 −/− cells formed bulky renal tumours dominated by immature mesenchyme and active canonical WNT/β‐catenin‐signalling. In contrast, IRX5 −/− cells displayed activation of Hippo and non‐canonical WNT‐signalling and generated small tumours with abundant tubulogenesis. Our findings suggest that promotion of IRX3 signalling or inhibition of IRX5 signalling could be a route towards differentiation therapy for Wilms tumour, in which WNT5A is a candidate molecule for enforced tubular maturation. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Canonical Wnt/β-catenin activity and differential epigenetic marks direct sexually dimorphic regulation of Irx3 and Irx5 in developing mouse gonads

“…Canonical Wnt/β-catenin signaling has been reported to promote Irx3 and Irx5 expression in the ovary (Naillat et al, 2010(Naillat et al, , 2015 and other tissues such as the brain (Braun et al, 2003), lung (Bell et al, 2008), neural axis (Janssens et al, 2010), kidney (Holmquist Mengelbier et al, 2019) and in colon cancer (Hovanes et al, 2001), but evidence for direct trans-acting regulation via DNA-binding partners has not been elucidated. Here, we used in vitro, ex vivo and in vivo approaches to provide a direct link between canonical Wnt/βcatenin signaling and Irx3 and Irx5 expression within the somatic cell population of the developing ovary.…”

Iroquois transcription factor irx2a is required for multiciliated and transporter cell fate decisions during zebrafish pronephros development

“…Three ancestral Irx genes— araucan , caupolican , and mirror —were originally identified in Drosophila melanogaster where they comprise the ‘Iro-C complex’ that controls segmentation of the body and regulates later formation of sense organs, the thorax, and wing vasculature 60,61 . Irx gene functions have been ascribed to many aspects of vertebrate organogenesis as well 37,38 , including the kidney 17,41–45,62 . During Xenopus embryonic kidney development, Irx1 and Irx3 have an early role in maintaining the pronephric territory 42 , and subsequently Irx3 is essential for intermediate nephron tubule fate, in part by controlling expression of Irx1 and Irx2 in renal progenitors 41 .…”

Shaping of the nephron – a complex, vulnerable, and poorly explored backdrop for noxae impairing nephrogenesis in the fetal human kidney

“…The outer border of the nephrogenic zone faces the inner side of the renal capsule ( Fig. 1), while the inner border lines along the proximal (medulla-orientated) pole of an Sshaped body [28,29,40].…”