The atypical cadherin Celsr3 regulates the development of the axonal blueprint

Celsr3, the murine orthologue of Drosophila Flamingo/Starry night, is a brain-specific, atypical sevenpass cadherin that plays a key role during brain development. Celsr3 mutant mice die at birth of central hypoventilation. They have major anomalies of major tracts, particularly absence of anterior commissure and of all components of the internal capsule. In addition, the medial lemniscus and several longitudinal bundles in the brainstem and spinal cord are defective. This phenotype is similar to that generated by inactivation of Frizzled3 (Fzd3). As both Flamingo and Frizzled are two core planar cell polarity (PCP) genes in flies, our results indicate that Celsr3 and Fzd3 are part of a genetic network with similarity to the PCP network. We studied by in situ hybridization the expression patterns of other murine PCP genes Dyl1-3, Vangl1,2 and Prickle1,2. Together with data from the literature, results suggest a mechanism whereby Celsr1-3, Fzd3 and 6, and Vangl2 may interact to control neural tube closure and axonal development. In order to study this mechanism further, we generated a conditional Celsr3 mutant mouse that allows inactivation of Celsr3 in the forebrain and cerebral cortex, by crossing with mice that express Cre under the Foxg1 and Emx1 promoters, respectively.