Pax-2 controls multiple steps of urogenital development

Abstract

Urogenital system development in mammals requires the coordinated differentiation of two distinct tissues, the ductal epithelium and the nephrogenic mesenchyme, both derived from the intermediate mesoderm of the early embryo. The former give rise to the genital tracts, ureters and kidney collecting duct system, whereas mesenchymal components undergo epithelial transformation to form nephrons in both the mesonephric (embryonic) and metanephric (definitive) kidney. Pax-2 is a transcriptional regulator of the paired-box family and is widely expressed during the development of both ductal and mesenchymal components of the urogenital system. We report here that Pax-2 homozygous mutant newborn mice lack kidneys, ureters and genital tracts. We attribute these defects to dysgenesis of both ductal and mesenchymal components of the developing urogenital system. The Wolffian and Mullerian ducts, precursors of male and female genital tracts, respectively, develop only partially and degenerate during embryogenesis. The ureters, inducers of the metanephros are absent and therefore kidney development does not take place. Mesenchyme of the nephrogenic cord fails to undergo epithelial transformation and is not able to form tubules in the mesonephros. In addition, we show that the expression of specific markers for each of these components is de-regulated in Pax-2 mutants. These data show that Pax-2 is required for multiple steps during the differentiation of intermediate mesoderm. In addition, Pax-2 mouse mutants provide an animal model for human hereditary kidney diseases.

The MLL3/4 H3K4 methyltransferase complex in establishing an active enhancer landscape

“…Several lines of studies suggest that PTIP involves in transcriptional regulation through facilitating the genomic recruitment of MLL3/4 complexes [24,[46][47][48]. PTIP was first discovered via its interactions with PAX2, a developmental regulator that specifies mesodermal cell fate determination and demarcates the midbrain-hindbrain junction [49,50]. By binding to PAX2, or a closely related PAX5, PTIP promoted the recruitment of MLL3/4 complexes and subsequent H3K4 methylation at PAX2/5-binding transcriptional regulatory regions [46,47].…”

It takes Two: Discovery of Spider Pax2 Duplicates Indicates Prominent Role in Chelicerate Central Nervous System, Eye, as Well as External Sense Organ Precursor Formation and Diversification After Neo- and Subfunctionalization

“…Surprisingly, apart from their role in sense organ development, Pax2/5/8 genes also take part in forming the vertebrate excretory system. The ureters as well as the genital tract are dependent on Pax2 for their formation and as a result, Pax2-deficient mice fail to form kidneys altogether (Torres et al, 1995). Data from lophotrochozoan species support a conserved function of Pax2 in sense organ development.…”

Studying Müllerian duct anomalies – from cataloguing phenotypes to discovering causation

“…This contrasts with the phenotype in chickens, in which Pax2 downregulation fully impairs invagination (Atsuta and Takahashi, 2016). In chicken, abrogating Pax2 expression almost completely depletes Lim1 expression; however, in the Pax2-deficient murine model, Lim1 is still upregulated in Müllerian mesoepithelial progenitors (Kobayashi et al, 2004;Torres et al, 1995;Atsuta and Takahashi, 2016). This explains the phenotypical dichotomy in Pax2 model systems, although additional findings can explain this phenomenon further.…”

“…A subset of epithelial progenitors also expresses the receptor for the anti-Müllerian hormone, Misr2 (also known as Amhr2; Box 1) (Ghosh et al, 2020). These Pax and homeobox members constitute an expression signature conserved among the epithelial lineages of the urogenital system, suggesting a role as master regulators controlling urogenital developmental programmes with potential co-regulation and cooperation (Pedersen et al, 2005;Bouchard et al, 2002Bouchard et al, , 2004Torres et al, 1995;Guioli et al, 2007;Vainio et al, 1999;Carroll et al, 2005;Barnes et al, 1994;Kobayashi et al, 2004;Davis et al, 2008;Miyamoto et al, 1997;Pellegrini et al, 1997;Grote et al, 2008). Furthermore, Müllerian progenitors also upregulate secreted proteins from the Wnt family (Box 1), such as Wnt7a in the epithelial precursors and Wnt4 in the mesenchymal ones (Vainio et al, 1999;Miller et al, 1998;Kobayashi et al, 2004).…”

“…Moreover, individuals with septate uterus had PAX2 hypomethylation and increased expression levels (Wang et al, 2020). In Pax2-null mouse models, Müllerian development is blocked soon after invagination due to the lack of Wolffian ducts (Kobayashi et al, 2004;Torres et al, 1995). This contrasts with the phenotype in chickens, in which Pax2 downregulation fully impairs invagination (Atsuta and Takahashi, 2016).…”