Atypical Cadherins Celsr1-3 Differentially Regulate Migration of Facial Branchiomotor Neurons in Mice

Abstract

During hindbrain development, facial branchiomotor neurons (FBM neurons) migrate from medial rhombomere (r) 4 to lateral r6. In zebrafish, mutations in planar cell polarity genes celsr2 and frizzled3a block caudal migration of FBM neurons. Here, we investigated the role of cadherins Celsr1-3, and Fzd3 in FBM neuron migration in mice. In Celsr1 mutants (knock-out and Crash alleles), caudal migration was compromised and neurons often migrated rostrally into r2 and r3, as well as laterally. These phenotypes were not caused by defects in hindbrain patterning or neuronal specification. Celsr1 is expressed in FBM neuron precursors and the floor plate, but not in FBM neurons. Consistent with this, conditional inactivation showed that the function of Celsr1 in FBM neuron migration was non-cell autonomous. In Celsr2 mutants, FBM neurons initiated caudal migration but moved prematurely into lateral r4 and r5. This phenotype was enhanced by inactivation of Celsr3 in FBM neurons and mimicked by inactivation of Fzd3. Furthermore, Celsr2 was epistatic to Celsr1. These data indicate that Celsr1-3 differentially regulate FBM neuron migration. Celsr1 helps to specify the direction of FBM neuron migration, whereas Celsr2 and 3 control its ability to migrate.

Roles of Planar Cell Polarity Signaling in Maturation of Neuronal Precursor Cells in the Postnatal Mouse Olfactory Bulb

“…Roles of the Wnt/PCP pathway in cell migration have been reported in several different contexts [24][25][26][27][28][29][30][31][32]. In this work, blocking the Wnt/PCP pathway decreased the number of NPCs that reached the OB, without affecting their differentiation or proliferation (Figs.…”

“…Furthermore, the migration of facial branchiomotor (FBM) neurons [24][25][26][27][28][29][30][31] and neural crest cells [32] depends on the function of the PCP genes, as does neuronal morphogenesis in the postnatal hippocampus [33,34] and OB [35], indicating that PCP signaling is involved in the migration and differentiation of many types of neural cells [36][37][38]. However, the function of this signaling pathway in the postnatal migration and differentiation of neurons in the OB has not been clearly demonstrated.…”

Zebrafish Prickle1b mediates facial branchiomotor neuron migration via a farnesylation-dependent nuclear activity

“…In future work, it will be essential to identify the transcriptional targets of REST and characterize their role in FBMN migration. Interestingly, a survey of the human genome (Johnson et al, 2007) has identified REST binding sites near several genes implicated in FBMN migration, including CELSR3 (Qu et al, 2010), contactin 2 (also known as TAG1) (Sittaramane et al, 2009) and those encoding components of the DAB1/reelin/CDK5 signaling pathway (Ohshima et al, 2002).…”

Planar cell polarity genes, Celsr1-3, in neural development

“…Recently, it was reported that Celsr1-3 work together to regulate facial branchiomotor neuron (FBM) migration [49] . Celsr1 is expressed in FBM neuron precursors and the floor plate, but not in FBM neurons, which helps to specify the direction of FBM neuron migration in a noncell autonomous manner.…”

“…Single-Celsr knockout mice show different phenotypes, such as the failure of axonal projections in Celsr3-/- [38] , abnormal organization of ependymal cilia in Celsr2-/- [50] , and improper neuronal migration in Celsr1-/- [49] . However, …”