The PAX2 tanscription factor is expressed in cystic and hyperproliferative dysplastic epithelia in human kidney malformations.

Abstract

Human dysplastic kidneys are developmental aberrations which are responsible for many of the very young children with chronic renal failure. They contain poorly differentiated metanephric cells in addition to metaplastic elements. We recently demonstrated that apoptosis was prominent in undifferentiated cells around dysplastic tubules (Winyard, P.J.D., J. Nauta, D.S. Lirenman, P. Hardman, V.R. Sams, R.A. Risdon, and A.S. Woolf. 1996. Kidney Int. 49:135-146), perhaps explaining the tendency of some of these organs to regress. In contrast, apoptosis was rare in dysplastic epithelia which are thought to be ureteric bud malformations. On occasion, these tubules form cysts which distend the abdominal cavity (the multicystic dysplastic kidney) and dysplastic kidneys may rarely become malignant. We now demonstrate that dysplastic tubules maintain a high rate of proliferation postnatally and that PAX2, a potentially oncogenic transcription factor, is expressed in these epithelia. In contrast, both cell proliferation and PAX2 are downregulated during normal maturation of human collecting ducts. We demonstrate that BCL2, a protein which prevents apoptosis in renal mesenchymal to epithelial conversion, is expressed ectopically in dysplastic kidney epithelia. We propose that dysplastic cyst formation may be understood in terms of aberrant temporal and spatial expression of master genes which are tightly regulated in the normal program of human nephrogenesis.

Growth and specification of the eye are controlled independently by Eyegone and Eyeless in Drosophila melanogaster

“…These observations are consistent with the view that the distinct roles of PAX6(5a) and PAX6 proteins shown here are not restricted to D. melanogaster. These studies should contribute to our understanding of PAX proteins in dorsal-ventral patterning of the central nervous system, somitogenesis, organogenesis, stem cell biology and human diseases 1,[5][6][7][8][9][10][11][12][13][14][15]45 . Scer\UAS.mg5603 ) and UAS-N ECD (N ECD.Scer\UAS ; two independent insertions on chromosome X and II).…”

“…Mutations in genes encoding Pax proteins not only disrupt organogenesis in fruit flies and mice 6 but also cause congenital disease syndromes in humans [5][6][7][8][9][10] , characterized by loss or hypoplasia of particular organs. Moreover, a growing body of evidence implicates deregulated expression of PAX genes in tissue-specific tumors in humans 5,6,[11][12][13][14][15] . The association between developmental defects and oncogenesis suggests that members of this family may mediate organ-specific growth in response to generic organizing signals.…”

Paired-Box genes are frequently expressed in cancer and often required for cancer cell survival

“…However, in a few adult tissues, PAX genes are expressed in a restricted fashion (Kozmik et al, 1993;St-Onge et al, 1997;Eccles, 1998). In contrast, abnormal cell growth and proliferation is associated with high levels of PAX gene expression in several diseases occurring in otherwise terminally differentiated tissues (Bernasconi et al, 1996;Winyard et al, 1996;Murer et al, 2002).…”

Unilateral multicystic dysplastic kidney in infants exposed to antiepileptic drugs during pregnancy

“…Therefore, in bcl-2 knockout mice, cystic renal formation may result from an inability of some renal cells to undergo terminal differentiation. Winyard et al [19] demonstrated that apoptosis is prominent in undifferentiated cells around dysplastic tubules; on the other hand, apoptosis is rare in dysplastic epithelia, which are thought to be ureteric bud malformations. Bcl-2 is consistently and ectopically expressed in dysplastic kidney epithelia.…”