NULL MUTATION OF MCOUP-TFI RESULTS IN DEFECTS IN MORPHOGENESIS OF THEGLOSSOPHARYNGEAL GANGLION, AXONAL PROJECTION, AND ARBORIZATION

The COUP-TFs are orphan members of the steroid/thyroid hormone recepto r superfamily. Multiple COUP-TF members have been cloned and they shar e a high degree of sequence homology between species as divergent as D rosophila and humans, suggesting a conservation of function through ev olution. The COUP-TFs are highly expressed in the developing nervous s ystems of several species examined, indicating their possible involvem ent in neuronal development and differentiation. In the mouse, there a re two very homologous COUP-TF genes (I and II) and their expression p atterns overlap extensively. To study the physiological function of mC OUP-TFI, a gene-targeting approach was undertaken. We report here that mCOUP-TFI null animals die perinataly. Mutant embryos display an alte red morphogenesis of the ninth cranial ganglion and nerve. The aberran t formation of the ninth ganglion is most possibly attributable to ext ra cell death in the neuronal precursor cell population. In addition, at midgestation, aberrant nerve projection and arborization were oberv ed in several other regions of mutant embryos. These results indicate that mCOUP-TFI is required for proper fetal development and is essenti al for postnatal development. Furthermore, mCOUP-TFI possesses vital p hysiological functions that are distinct from mCOUP-TFII despite of th eir high degree of homology and extensive overlapping expression patte rns.