Prickle1 is necessary for the caudal migration of murine facial branchiomotor neurons

Abstract

Facial branchiomotor neurons (FBMs) of vertebrates typically develop in rhombomere 4 (r4) and in mammals and several other vertebrate taxa, migrate caudally into r6 and subsequently laterally and ventrally to the pial surface. How similar or dissimilar these migratory processes between species are at a molecular level remains unclear. In zebrafish and mouse, mutations in certain PCP genes disrupt normal caudal migration of FBMs. Zebrafish prickle1a (prickle-like 1a) and prickle1b, two orthologs of Prickle1, act non-cell autonomously and cell-autonomously, respectively, to regulate FBM migration. Here we show that in Prickle1C251X/C251X mice, which have reduced Prickle1 expression, the caudal migration of FBMs is affected. Most FBM neurons do not migrate caudally along the floor plate. However, some neurons perform limited caudal migration such that the neurons eventually lie near the pial surface from r4 to anterior r6. FBMs in Prickle1C251X/C251X mice survive until P0 and form an ectopic nucleus dorsal to the olivo-cochlear efferents of r4. Ror2, which modifies the PCP pathway in other systems, is expressed by the migrating mouse FBMs, but is not required for FBM caudal migration. Our results suggest that in mice, Prickle1 is part of a molecular mechanism that regulates FBM caudal migration and separates the FBM and the olivo-cochlear efferents. This defective caudal migration of FBMs in Prickle1C251X mutants resembles Vangl2 mutant defects. In contrast to other developing systems that show similar defects in Prickle1, Wnt5a and Ror2, Wnt5a and Ror2 only have limited or no effect on FBM caudal migration.

Ade novomutation inPRICKLE1in fetal agenesis of the corpus callosum and polymicrogyria

“…Neurological phenotypes including epilepsy(Tao, Manak et al 2011) and learning abnormalities(Paemka, Mahajan et al 2013) and neuronal migration abnormalities have been described in multiple animal models of PRICKLE1 mutations(Bosoi, Capra et al 2011; Tao, Manak et al 2011; Mei, Wu et al 2013; Paemka, Mahajan et al 2013; Ehaideb, Iyengar et al 2014; Yang, Bassuk et al 2014) yet to our knowledge, a de novo mutation in human PRICKLE1 had yet to be reported. Our description of a de novo PRICKLE1 mutation associated with agenesis of the corpus calllosum and polymicrogyria in the absence of any other de novo mutation or known disease causing mutation strongly implicates the PRICKLE1 gene as causative of the severe cerebral malformation in this fetus.…”

“…Subsequently, several studies have identified neurological abnormalities in animal models with both heterozygous and homozygous mutations in PRICKLE1 orthologues, including epilepsy in flies and in mice with heterozygous PRICKLE1 mutations(Bosoi, Capra et al 2011; Tao, Manak et al 2011; Paemka, Mahajan et al 2013; Ehaideb, Iyengar et al 2014). Neuronal migration abnormalities have also been reported in several animal models of PRICKLE1 mutations(Tao, Manak et al 2011; Yang, Bassuk et al 2014). While heterozygous PRICKLE1 mutations have been reported in several human conditions including epilepsy(Tao, Manak et al 2011), autism(Paemka, Mahajan et al 2013) and spina bifida(Bosoi, Capra et al 2011), these mutations have all been inherited (or inheritance was not determined).…”

Planar cell polarity in moving cells: think globally, act locally

“…This finding stems primarily from studies of mouse and zebrafish facial branchiomotor neurons (FBMNs), which originate ventrally in hindbrain rhombomere (r)4 and undergo highly stereotypical posterior migration along the floorplate to r6 and r7 (Wanner et al, 2013). Mutations in the genes encoding Vangl2, Pk1, Fz3 and Celsr2 all prevent FBMN migration in zebrafish and mice, as do Scrib and Ptk7 mutations Glasco et al, 2012;Mapp et al, 2011;Qu et al, 2010;Vivancos et al, 2009;Wada et al, 2005Wada et al, , 2006Yang et al, 2014) (Table 1). The role of Wnt ligands in FBMN migration is uncertain: mice lacking Wnt5a have a mild defect whereas Wnt4a, Wnt5a and Wnt11r mutants in zebrafish all exhibit normal FBMN migration (Vivancos et al, 2009) (our unpublished results).…”

The atypical cadherin Celsr1 functions non-cell autonomously to block rostral migration of facial branchiomotor neurons in mice

“…While many PCP genes such as Celsr1-3, fzd3a, Pk1, Ptk7, Scrb, Vangl2, and Wnt5a are necessary for proper migration of FBM neurons into r6 (Carreira-Barbosa et al, 2003; Glasco et al, 2012; Mapp et al, 2010; Qu et al, 2010; Vivancos et al, 2009; Wada et al, 2006, 2005; Yang et al, 2014), other genes such as Dvl1-2 and glypican4/6 are not (Bingham et al, 2002; Glasco et al, 2012; Jessen et al, 2002; however, see also Davey et al, 2016), suggesting that caudal migration of FBM neurons is a PCP-independent process. Interestingly, one PCP gene, the atypical cadherin Celsr1, has been shown to regulate the directionality of FBM migration in mice (Glasco et al, 2012; Qu et al, 2010).…”