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. 1996 Nov 26;93(24):13870-5.
doi: 10.1073/pnas.93.24.13870.

The mouse Pax2(1Neu) mutation is identical to a human PAX2 mutation in a family with renal-coloboma syndrome and results in developmental defects of the brain, ear, eye, and kidney

J Favor  1 , R Sandulache, A Neuhäuser-Klaus, W Pretsch, B Chatterjee, E Senft, W Wurst, V Blanquet, P Grimes, R Spörle, K Schughart
Affiliations

The mouse Pax2(1Neu) mutation is identical to a human PAX2 mutation in a family with renal-coloboma syndrome and results in developmental defects of the brain, ear, eye, and kidney

J Favor et al. Proc Natl Acad Sci U S A. .

Abstract

We describe a new mouse frameshift mutation (Pax2(1Neu)) with a 1-bp insertion in the Pax2 gene. This mutation is identical to a previously described mutation in a human family with renal-coloboma syndrome [Sanyanusin, P., McNoe, L. A., Sullivan, M. J., Weaver, R. G. & Eccles, M. R. (1995) Hum. Mol. Genet. 4, 2183-2184]. Heterozygous mutant mice exhibit defects in the kidney, the optic nerve, and retinal layer of the eye, and in homozygous mutant embryos, development of the optic nerve, metanephric kidney, and ventral regions of the inner ear is severely affected. In addition, we observe a deletion of the cerebellum and the posterior mesencephalon in homozygous mutant embryos demonstrating that, in contrast to mutations in Pax5, which is also expressed early in the mid-hindbrain region, loss of Pax2 gene function alone results in the early loss of the mid-hindbrain region. The mid-hindbrain phenotype is similar to Wnt1 and En1 mutant phenotypes, suggesting the conservation of gene regulatory networks between vertebrates and Drosophila.

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Figures

Figure 1
Figure 1
Chromosomal mapping of the K289 mutation to the distal region of chromosome 19 and sequence analysis of the mutant Pax21Neu allele. (A) Distribution of haplotypes in backcross animals. Solid boxes, C3H allele; open boxes, C57BL/6 allele. (B) Schematic presentation of distal chromosome 19. (C) Partial sequence of the wild-type and mutant Pax21Neu alleles.
Figure 2
Figure 2
Eye defects in heterozygous Pax21Neu mice. Retinal morphology of adult (3–6 months of age) wild-type (A and C) and heterozygous (B and D) mice. In comparison to the normal eye (A), note the broad and cup-shaped optic disc in the heterozygote (B) and pronounced thinning of all neural layers of the adjacent retina (arrow). An arterial vessel (AV) projects into the vitreous; a small branch vessel (arrowhead) arches to the surface of the retina. Beyond the immediate region of the optic disc, the inner retinal layers of the heterozygous eye (D) are still markedly thinned, but the photoreceptor layer is similar in thickness to that in the normal eye (C). Preretinal vessels (arrow) are visible all along the inner surface of the mutant retina (D). (Bars = 100 μm.)
Figure 3
Figure 3
Defects in development of the mid-hindbrain region in Pax21Neu mutant embryos. Wild-type (A, C, and E) and mutant (B, D, and F) embryos. (A and B) Overview of head region of TS21 embryos. The mid-hindbrain junction (isthmus) is clearly visible in wild-type (A) (arrow) but absent in mutant (B) embryos. (C and D) Sagittal sections through head regions of TS23 embryos. The anlagen of the cerebellum and most parts of the mesencephalon are missing in mutant embryos whereas the pons appears to be unaffected (D). (E and F) TS15 whole-mount embryos hybridized with an En2-specific RNA probe. In wild-type, En2 is expressed in a broad band across the mid-hindbrain region (E) (arrowheads). In mutants (F), En2 expression was greatly reduced to a small region in the dorsal neural tube. IV, fourth ventricle; CB, cerebellum; CP, choroid plexus; ME, mesencephalon; MY, myelencephalon; P, pons; TE, telencephalon. (C and D, bars = 500 μm.)
Figure 4
Figure 4
Defects in development of the inner ear, eye, and nephrogenic mesenchyme in Pax21Neu mutant embryos. Tissue sections from wild-type (A, C, E, and G) and mutant (B, D, F, and H) TS23 embryos. The inner ear in wild-type embryos showed development of the cochlea and its associated ganglion (A). In Pax2 mutant embryos, formation of a distinct cochlea anlagen could not be found (B). Instead, a large chamber was observed that continued into an enlarged endolymphatic duct (B) (asterisk). Cross sections through the optic nerve of wild-type (C and E) and homozygous mutant (D and F) embryos. In mutant embryos, axon fibers were found inside the optic stalk (D) and single isolated axon fascicles could be observed in the ventral, lateral, or dorsal wall of the optic stalk (D) (arrow). In more proximal optic stalk regions of homozygous embryos, most axon fibers were seen in the posterior region of the optic stalk (F). (G and H) Sections through urogenital tract of TS23 embryos. In mutant embryos, adrenal and gonad were present, but only a small anlagen of the presumptive metanephrogenic blastema was detectable (H) (arrow). Formation of tubules could not be seen in this mesenchyme. AD, adrenal gland; CG, cochlear ganglion; CO, cochlea; ED, endolymphatic duct; K, metanephric kidney; O, ovary; ON, optic nerve; OS, optic stalk; T, testis. (A, B, G, and H, bar = 200 μm; C–F, bar = 50 μm.)
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