The Pax2, Pax5 and Pax8 genes are expressed in a spatially and temporally overlapping manner at the midbrain-hindbrain boundary (MHB) and in the spinal cord of the mouse embryo

The duplication of developmental control genes has been a driving force in evolution to increase the diversity and complexity of higher eukaryotes. One of these multigene families codes for the Pax transcription factors, which can be divided into four distinct subclasses based on their sequence similarities (Noll, 1993; Mansouri et al., 1996). The vertebrate Pax2, Pax5 and Pax8 genes constitute one such subclass, which has been even further diversified during zebrafish evolution by a recent Pax2 gene duplication (Pfeffer et al., 1998). The genome of most invertebrates, however, contains only a single Pax2/5/8 gene (Czerny et al., 1997; Fu and Noll, 1997; Wada et al., 1998; Kozmik et al., 1999), indicating that the complexity of this Pax subfamily has arisen by gene duplications at the onset of vertebrate evolution. Structure-function analyses revealed that the mammalian Pax2, Pax5 and Pax8 proteins possess similar biochemical activities. For instance, the DNA-binding specificity of these proteins is highly similar due to extreme sequence conservation of the N-terminal paired domain (Adams et al., 1992; Kozmik et al., 1993; Czerny et al., 1997). All three proteins, furthermore, contain a conserved transactivation domain at the C terminus (Dörfler and Busslinger, 1996; Lechner and Dressler, 1996) as well as a partial homeodomain, which constitutes an interaction surface for the retinoblastoma (Rb) and TATA-binding (TBP) proteins (Eberhard and Busslinger, 1999). The three Pax proteins are also able to negatively regulate gene transcription by utilizing a conserved octapeptide motif for recruitment of Groucho corepressor proteins (Eberhard et al., 2000). The Pax2, Pax5 and Pax8 genes are expressed in a spatially and temporally overlapping manner at the midbrain-hindbrain boundary (MHB) and in the spinal cord of the mouse embryo (Nornes et al., 1990; Plachov et al., 1990; Adams et al., 1992; Asano and Gruss, 1992). Outside the CNS, Pax2 and Pax8 are coexpressed only in the mesenchymal aggregates and derived tubular structures of the developing kidney (Dressler et al., 1990; Plachov et al., 1990). The Pax2 gene is uniquely expressed in most tissues of the developing urogenital system as well as during eye and inner ear development (Dressler et al., 1990; Nornes et al., 1990), Pax5 during B-lymphopoiesis (Adams et al., 1992) and Pax8 in the developing thyroid gland (Plachov et al., 1990). Consistent with these expression patterns, targeted gene inactivation resulted in severe phenotypes, primarily in the unique expression domains of these Pax genes. The loss of Pax2 results in pathfinding defects of the optic nerve, extension of the pigmented retina into the optic stalk and lack of optic fissure closure during eye development, in the absence of kidney, ureter and genital tracts 3703 Development 127, 3703-3713 (2000) Printed in Great Britain © The Company of Biologists Limited 2000 DEV2587