ErbB4 Modulates Tubular Cell Polarity and Lumen Diameter... : Journal of the American Society of Nephrology (original) (raw)

Basic Research

ErbB4 Modulates Tubular Cell Polarity and Lumen Diameter during Kidney Development

Veikkolainen, Ville*,†; Naillat, Florence‡; Railo, Antti‡; Chi, Lijun‡; Manninen, Aki‡; Hohenstein, Peter§; Hastie, Nick§; Vainio, Seppo‡; Elenius, Klaus*,‖

*Department of Medical Biochemistry and Genetics and MediCity Research Laboratory, University of Turku, Turku, Finland;

†Turku Graduate School of Biomedical Sciences, Turku, Finland;

‡Oulu Centre for Cell-Matrix Research, Biocenter Oulu, Laboratory of Developmental Biology and Department of Medical Biochemistry and Molecular Biology, University of Oulu, Oulu, Finland;

§MRC Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom; and

‖Department of Oncology, Turku University Hospital, Turku, Finland

V.V. and F.N. contributed equally to this work.

Correspondence: Dr. Klaus Elenius, Department of Medical Biochemistry and Genetics, University of Turku, Kiinamyllynkatu 10, FIN-20520 Turku, Finland. Email: [email protected]

Received February 15, 2011

Accepted August 17, 2011

Abstract

ErbB4 receptor tyrosine kinase contributes to the development of the heart, the central nervous system, and the lactating mammary gland, but whether it has a role in the development of the kidney epithelium is unknown. Here, we found that expression of Erbb4 isoforms JM-a CYT-1 and JM-a CYT-2 was first detectable around embryonic day 13 in the mouse, mainly in the collecting ducts and both the proximal and distal tubules. In vitro, overexpression of a relevant ErbB4 isoform promoted proliferation and disturbed polarization of kidney epithelial cells when cultured as three-dimensional structures. We examined ErbB4 function in developing kidney tubules in vivo with _Pax8-Cre_–mediated conditional overexpression of Rosa26 locus–targeted ERBB4 and with conditional Erbb4 knock-out mice. The _Pax8-Cre_–driven ERBB4 overexpression enhanced proliferation in the collecting ducts, reduced the size of epithelial duct lumens, and promoted formation of cortical tubular cysts. These defects were associated with changes in the subcellular distribution of markers of epithelial cell polarity. Similarly, the _Pax8-Cre_–mediated Erbb4 knock-out mice manifested dysfunctional kidneys with larger duct lumens and epithelial cell mispolarization. Taken together, these data suggest that ErbB4 signaling modulates proliferation and polarization, cellular functions critical for the development of epithelial ducts in the kidney.