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Dev Biol. 2001 Jun 1;234(1):244-60.

The Wheels mutation in the mouse causes vascular, hindbrain, and inner ear defects.

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  • 1Department of Psychiatry and Genetics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.


In a screen for mouse mutations with dominant behavioral anomalies, we identified Wheels, a mutation associated with circling and hyperactivity in heterozygotes and embryonic lethality in homozygotes. Mutant Wheels embryos die at E10.5-E11.5 and exhibit a host of morphological anomalies which include growth retardation and anomalies in vascular and hindbrain development. The latter includes perturbation of rhombomeric boundaries as detected by Krox20 and Hoxb1. PECAM-1 staining of embryos revealed normal formation of the primary vascular plexus. However, subsequent stages of branching and remodeling do not proceed normally in the yolk sac and in the embryo proper. To obtain insights into the circling behavior, we examined development of the inner ear by paint-filling of membranous labyrinths of Whl/+ embryos. This analysis revealed smaller posterior and lateral semicircular canal primordia and a delay in the canal fusion process at E12.5. By E13.5, the lateral canal was truncated and the posterior canal was small or absent altogether. Marker analysis revealed an early molecular phenotype in heterozygous embryos characterized by perturbed expression of Bmp4 and Msx1 in prospective lateral and posterior cristae at E11.5. We have constructed a genetic and radiation hybrid map of the centromeric portion of mouse Chromosome 4 across the Wheels region and refined the position of the Wheels locus to the approximately 1.1-cM region between D4Mit104 and D4Mit181. We have placed the locus encoding Epha7, in the Wheels candidate region; however, further analysis showed no mutations in the Epha7-coding region and no detectable changes in mRNA expression pattern. In summary, our findings indicate that Wheels, a gene which is essential for the survival of the embryo, may link diverse processes involved in vascular, hindbrain, and inner ear development.

Copyright 2001 Academic Press.

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