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Neurogenetics

Two mouse homeobox containing engrailed genes (En-1, En-2) have been identified based on their sequence similarity to the Drosophila engrailed and invected genes. Both genes are expressed from 8.5dpc in a band across the neuroepithelium which will give rise to the mid-hindbrain region. From 9.5dpc En-1 is also expressed in the developing somites, spinal cord and limb buds.
To study the function of these genes during embryonic development we created mutations in both genes by homologous recombination. Mice homozygous for a homeobox deletion (En-2hd/hd) or a null mutation (En-2ntd/ntd) in the En-2 gene are viable but have patterning defects in the adult cerebellum. In contrast, mice homozygous for a homeobox deletion in the En-1 gene (En-1hd/hd) die at birth and display multiple developmental defects: deletion of mid-hindbrain tissue and patterning defects of the developing forelimbs and sternum. The brain defect is morphologically visible by 9.5dpc.
Considering the similarity in protein structure and expression pattern of En-1 and En-2, the difference in severity of the two mutant phenotypes was unexpected. To determine, whether En-2 plays a role similar to En-1 in early mid-hindbrain development we generated compound heterozygous and homozygous mice. Interestingly, mice carrying the genotype En-1hd/hd; En-2hd/+ or En-1hd/+; En-2hd/hd show more severe phenotypes than En-1hd/hd or En-2hd/hd mutant mice respectively. Mice carrying homozygous mutations in both En genes (En-1hd/hd; En-2hd/hd) display the most severe deletion of mid-hindbrain tissue shown by histology and by using mid-hindbrain markers. These results suggest that there is a gene dosage effect of En genes on mid-hindbrain development and a functional overlap between the closely related En-2 and En-l genes. Furthermore, the En compound homozgous mutant brain phenotype resembles the Wnt-1 mutant phenotype suggesting that an engrailed/wingless interaction might be conserved in mammals.



Headings
engrailed genes (En-1, En-2)
mid-hindbrain development

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