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

Abstract

SUMMARYThe facial branchiomotor neurons (FBMNs) undergo a characteristic tangential migration in the vertebrate hindbrain. We previously used a morpholino knockdown approach to reveal that zebrafish prickle1b (pk1b) is required for this migration. Here we report that FBMN migration is also blocked in a pk1b mutant with a disruption in the consensus farnesylation motif. We confirmed that this lipid modification is required during FBMN migration by disrupting the function of farnesyl biosynthetic enzymes. Furthermore, farnesylation of a tagged Pk1b is required for its nuclear localization. Using a unique rescue approach, we have demonstrated that Pk1b nuclear localization and farnesylation are required during FBMN migration. Our data suggest that Pk1b acts at least partially independently of core planar cell polarity molecules at the plasma membrane, and might instead be acting at the nucleus. We also found that the neuronal transcriptional silencer REST is necessary for FBMN migration, and we provide evidence that interaction between Pk1b and REST is required during this process. Finally, we demonstrate that REST protein, which is normally localized in the nuclei of migrating FBMNs, is depleted from the nuclei of Pk1b-deficient neurons. We conclude that farnesylation-dependent nuclear localization of Pk1b is required to regulate REST localization and thus FBMN migration.

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.…”

Structural and temporal requirements of Wnt/PCP protein Vangl2 function for convergence and extension movements and facial branchiomotor neuron migration in zebrafish

“…Several genes in zebrafish have demonstrated roles in FBM neuron migration from rhombomere 4 (r4) to r6 and r7, including those encoding transcription factors Hoxb1b (McClintock et al, 2002) and MafB (Chandrasekhar et al, 1997), chromatin regulatory proteins Hdac1 (Nambiar et al, 2007) and REST (Mapp et al, 2011), elongation factor Foggy/Spt5 (Cooper et al, 2005), stromal cell-derived factor Sdf1a and its receptors CxcR4 and CxcR7 (Cubedo et al, 2009), the autism susceptibility protein Met and its Hgf ligand (Elsen et al, 2009), adhesion GPCR gp125 (Li et al, 2013), the cell adhesion molecule Tag1 (Sittaramane et al, 2009), Integrinα6 (V.S. and A.C., unpublished data), and extracellular matrix molecules, Lamininα1 and γ1 (Sittaramane et al, 2009; Grant and Moens, 2010; V.S.…”

“…We and others have shown that the Wnt receptor Frizzled3a (Wada et al, 2006), the transmembrane protein Vangl2 (Bingham et al, 2002; Jessen et al, 2002), atypical cadherins Celsr 1a, 1b, and 2 (Wada et al, 2006), cytoplasmic adaptors Prickle1a (Carreira-Barbosa et al, 2003), Prickle1b (Mapp et al, 2010), and Scribble (Wada et al, 2005), but not Glypican 4/6 (Bingham et al, 2002) or core signaling molecule Disheveled (Dvl) (Jessen et al, 2002; Glasco et al, 2012), are necessary for caudal migration of FBM neurons. Interestingly, Prickle1b acts in part through REST, likely in a PCP-independent pathway (Mapp et al, 2011). Furthermore, vangl2 interacts genetically with non-PCP genes like tag1 , lamininα1 , itgα6 , and hdac1 (Nambiar et al, 2007; Sittaramane et al, 2009; V.S.…”

Functional characterization of Prickle2 and BBS7 identify overlapping phenotypes yet distinct mechanisms

“…Bbs7 mouse knockouts display defects in photoreceptors, brain ependymal cilia and sperm flagella (Zhang et al, 2013). Pk is a core component of PCP and modulates CE and neuronal outgrowth (Jiang et al, 2005; Mapp et al, 2011; Mapp et al, 2010; Mei et al, 2013; Ng, 2012; Tada et al, 2003; Takeuchi et al, 2003; Tree et al, 2002; Veeman et al, 2003). Mutation in PK1 and PK2 were identified in human epilepsy patients and loss of pk also contributes to seizure-like phenotype in mice, flies and zebrafish (Bassuk et al, 2008; Mei et al, 2013; Tao et al, 2011).…”