Nephric lineage specification by Pax2 and Pax8

Abstract

The mammalian kidney develops in three successive steps from the initial pronephros via the mesonephros to the adult metanephros. Although the nephric lineage is specified during pronephros induction, no single regulator, including the transcription factor Pax2 or Pax8, has yet been identified to control this initial phase of kidney development. In this paper, we demonstrate that mouse embryos lacking both Pax2 and Pax8 are unable to form the pronephros or any later nephric structures. In these double-mutant embryos, the intermediate mesoderm does not undergo the mesenchymal-epithelial transitions required for nephric duct formation, fails to initiate the kidney-specific expression of Lim1 and c-Ret, and is lost by apoptosis 1 d after failed pronephric induction. Conversely, retroviral misexpression of Pax2 was sufficient to induce ectopic nephric structures in the intermediate mesoderm and genital ridge of chick embryos. Together, these data identify Pax2 and Pax8 as critical regulators that specify the nephric lineage.

Pax2 modulates proliferation during specification of the otic and epibranchial placodes

“…During inner ear induction in zebrafish, Xenopus, and mouse, Pax8 and Pax2 are both expressed in the inner ear, and their function in early inner ear induction is thought to be redundant (Heller and Brandli, 1999;Bouchard et al, 2002;Hans et al, 2004;Mackereth et al, 2005). We find that in the lineage that leads to birds and lizards, the Pax8 gene has been lost.…”

“…In most vertebrates, Pax8 is considered to be one of the earliest markers of otic fate (Bouchard et al, 2002;Hans et al, 2004;Mackereth et al, 2005). We thus attempted to clone Gallus Pax8 from the 4ss/HH8 presumptive inner ear region cDNA using RT-PCR.…”

“…Similarly the activity of Pax6 is involved in conferring progenitor status to neuronal populations in the spinal cord, cerebral cortex, adult hippocampus, and olfactory bulb (Grindley et al, 1995;Kohwi et al, 2005;Bel-Vialar et al, 2007;Tucker et al, 2008). Similarly, the expression of Pax2 and Pax8 is associated with proliferating progenitor populations in the developing kidney (Bouchard et al, 2002) and in the sensory patches of the inner ear (Li et al, 2004;Warchol and Richardson, 2009). Thus, the activity of Pax2 in the PPA is consistent with the generalized model of Pax function that has emerged (Blake et al, 2008).…”

“…Pax2 groups with Pax5 and Pax8, and in many regions of the embryo either two or all three of the Pax2/5/8 sub-family, are co-regulated (Krelova et al, 2002). In most vertebrates, the mid-hindbrain boundary expresses all three genes, although the kidney and inner ear primordia only express Pax2 and Pax8 (Plachov et al, 1990;Stoykova and Gruss, 1994;Lun and Brand, 1998;Pfeffer et al, 1998;Funahashi et al, 1999;Kozmik et al, 1999;Bouchard et al, 2002;Krelova et al, 2002;Hans et al, 2004), with Pax5 not present in these tissues (Funahashi et al, 1999;Kwak et al, 2006). The overlap between Pax2 and Pax8 in the PPA has confounded functional characterization of this Pax subfamily due to their presumed redundancy.…”

“…Functional analysis has not provided conclusive evidence of the mechanistic role of Pax2/8 genes during inner ear and epibranchial development. Despite its earlier expression, mice mutant for only Pax8 do not show an overt inner ear phenotype (Bouchard et al, 2002). Pax2 mutants do show a later otic phenotype with malformations of the inner ear apparent in mice at E12, well after the inner ear has invaginated and closed (Torres et al, 1996;Burton et al, 2004).…”