Role of WntPlanar cell polarity genes in migration of facial branchiomotor neurons
Abstract
During brain development, newborn neurons must migrate to precise locations in order to establish functional circuitry. Defective neuronal migration underlies several human brain disorders. The facial branchiomotor (FBM) neurons providing an intriguing model to examine neuronal migration mechanisms. Migration of these neurons requires the function of components of the Wnt/Planar Cell Polarity (PCP) signaling pathway. In the mouse, these neurons are born in rhombomere 4 (r4) of the hindbrain, and migrate caudally into r6 to form the facial motor nucleus. In mice carrying mutations in the gene encoding the Wnt/PCP cadherin Ceslr1, caudal migration is intact, but a significant subset of neurons inappropriately migrates rostrally, suggesting that Celsr1 regulates the directionality of migration. Tissue-specific Celsr1 knockouts indicate that Celsr1 likely functions within the ventricular zone of rhombomeres 3 and 4. These and other data suggest that Wnt-mediated signaling may inappropriately attract FBM neurons into r3 in Celsr1 mutants, and that such attraction is normally suppressed in wild type embryos. In Celsr1 mutants, the inactivation of Dvl suppresses the rostral migration phenotype, suggesting that rostral migration is Dvl-dependent. Therefore, we hypothesized that FBM neurons can potentially respond to the chemoattractant Wnt5a in r3 through a Dvl-dependent pathway, but that Celsr1 in the rostral hindbrain normally suppresses Wnt activity, preventing inappropriate rostral migration. FBM neurons of wild type mice can be attracted towards ectopic sources of Wnt5a placed in the rostral hindbrain. Consistent with our hypothesis, migration of FBM neurons towards Wnt5a coated beads placed in r3 in Dvl2-/- hindbrain explants was greatly reduced compared to migration in Dvl2+/+ and Dvl2+/- explants. Thus it appears that the suppression of responsiveness to Wnt5a could be preventing the neurons from responding to the chemoattractant signal in r3 and blocking rostral migration. If Celsr1 is acting in r3 and r4 to su
Degree
M.A.