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

Holmquist Mengelbier, Linda LU ; Lindell-Munther, Simon ; Yasui, Hiroaki LU ; Jansson, Caroline LU ; Esfandyari, Javanshir LU ; Karlsson, Jenny LU ; Lau, Kimberly ; Hui, Chi chung ; Bexell, Daniel LU and Hopyan, Sevan , et al. (2019) In Journal of Pathology 247(1).
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,... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
differentiation, Iroquois, IRX3, IRX5, nephrogenesis, Wilms tumour, WNT5A
in
Journal of Pathology
volume
247
issue
1
publisher
John Wiley & Sons Inc.
external identifiers
  • scopus:85057796746
  • pmid:30246301
ISSN
0022-3417
DOI
10.1002/path.5171
language
English
LU publication?
yes
id
dffe7379-e7b4-4204-8955-04121bac7ff4
date added to LUP
2018-12-21 13:27:10
date last changed
2024-04-29 20:42:47
@article{dffe7379-e7b4-4204-8955-04121bac7ff4,
  abstract     = {{<p>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<sup>−</sup>/Irx5<sup>−</sup> 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<sup>−/−</sup> cells formed bulky renal tumours dominated by immature mesenchyme and active canonical WNT/β-catenin-signalling. In contrast, IRX5<sup>−/−</sup> 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.</p>}},
  author       = {{Holmquist Mengelbier, Linda and Lindell-Munther, Simon and Yasui, Hiroaki and Jansson, Caroline and Esfandyari, Javanshir and Karlsson, Jenny and Lau, Kimberly and Hui, Chi chung and Bexell, Daniel and Hopyan, Sevan and Gisselsson, David}},
  issn         = {{0022-3417}},
  keywords     = {{differentiation; Iroquois; IRX3; IRX5; nephrogenesis; Wilms tumour; WNT5A}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Journal of Pathology}},
  title        = {{The Iroquois homeobox proteins IRX3 and IRX5 have distinct roles in Wilms tumour development and human nephrogenesis}},
  url          = {{http://dx.doi.org/10.1002/path.5171}},
  doi          = {{10.1002/path.5171}},
  volume       = {{247}},
  year         = {{2019}},
}