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

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The Iroquois homeobox proteins IRX3 and IRX5 have distinct roles in Wilms tumour development and human nephrogenesis. / Holmquist Mengelbier, Linda; Lindell-Munther, Simon; Yasui, Hiroaki; Jansson, Caroline; Esfandyari, Javanshir; Karlsson, Jenny; Lau, Kimberly; Hui, Chi chung; Bexell, Daniel; Hopyan, Sevan; Gisselsson, David.

In: Journal of Pathology, Vol. 247, No. 1, 01.2019.

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T1 - The Iroquois homeobox proteins IRX3 and IRX5 have distinct roles in Wilms tumour development and human nephrogenesis

AU - Holmquist Mengelbier, Linda

AU - Lindell-Munther, Simon

AU - Yasui, Hiroaki

AU - Jansson, Caroline

AU - Esfandyari, Javanshir

AU - Karlsson, Jenny

AU - Lau, Kimberly

AU - Hui, Chi chung

AU - Bexell, Daniel

AU - Hopyan, Sevan

AU - Gisselsson, David

PY - 2019/1

Y1 - 2019/1

N2 - 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.

AB - 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.

KW - differentiation

KW - Iroquois

KW - IRX3

KW - IRX5

KW - nephrogenesis

KW - Wilms tumour

KW - WNT5A

U2 - 10.1002/path.5171

DO - 10.1002/path.5171

M3 - Article

VL - 247

JO - Journal of Pathology

T2 - Journal of Pathology

JF - Journal of Pathology

SN - 0022-3417

IS - 1

ER -