MULTIPLE DEVELOPMENTAL DEFECTS IN ENGRAILED-1 MUTANT MICE - AN EARLY MID-HINDBRAIN DELETION AND PATTERNING DEFECTS IN FORELIMBS AND STERNUM

During mouse development, the homeobox-containing gene En-1 is specifi cally expressed across the mid-hindbrain junction, the ventral ectoder m of the limb buds, and in regions of the hindbrain, spinal cord, somi tes and somite-derived tissues. To address the function of En-1 during embryogenesis, we have generated mice homozygous for a targeted delet ion of the En-1 homeobox. En-1 mutant mice died shortly after birth an d exhibited multiple developmental defects. In the brains of newborn m utants, most of the colliculi and cerebellum were missing and the thir d and fourth cranial nerves were absent. A deletion of mid-hindbrain t issue was observed as early as 9.5 days of embryonic development and t he phenotype resembles that previously reported for Wnt-1 mutant mice. In addition, patterning of the forelimb paws and sternum was disrupte d, and the 13th ribs were truncated. The results of these studies sugg est a cell autonomous role for En-1 in generation and/or survival of m id-hindbrain precursor cells and also a non-cell autonomous role in si gnaling normal development of the limbs and possibly sternum.