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Development
2014 Aug 01;14116:3153-8. doi: 10.1242/dev.111427.
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Vangl-dependent planar cell polarity signalling is not required for neural crest migration in mammals.
Pryor SE
,
Massa V
,
Savery D
,
Andre P
,
Yang Y
,
Greene ND
,
Copp AJ
.
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The role of planar cell polarity (PCP) signalling in neural crest (NC) development is unclear. The PCP dependence of NC cell migration has been reported in Xenopus and zebrafish, but NC migration has not been studied in mammalian PCP mutants. Vangl2(Lp/Lp) mouse embryos lack PCP signalling and undergo almost complete failure of neural tube closure. Here we show, however, that NC specification, migration and derivative formation occur normally in Vangl2(Lp/Lp) embryos. The gene family member Vangl1 was not expressed in NC nor ectopically expressed in Vangl2(Lp/Lp) embryos, and doubly homozygous Vangl1/Vangl2 mutants exhibited normal NC migration. Acute downregulation of Vangl2 in the NC lineage did not prevent NC migration. In vitro, Vangl2(Lp/Lp) neural tube explants generated emigrating NC cells, as in wild type. Hence, PCP signalling is not essential for NC migration in mammals, in contrast to its essential role in neural tube closure. PCP mutations are thus unlikely to mediate NC-related birth defects in humans.
Fig. 1. Normal pattern of NC cell migration in Vangl2Lp/Lp mouse embryos. Migrating NC detected by Erbb3 mRNA expression (A-F) and YFP expression regulated by Wnt1-Cre (G-N). Wild-type (+/+; A-C,G-J) and Vangl2Lp/Lp (Lp/Lp; D-F,K-N) embryos at early E9.5 (13-14 somites) both exhibit NC cells colonising forebrain, peri-ocular region (A,D, arrows) and upper branchial arches (ba). Transverse sections show branchial arch colonisation (B,E,H,I,L,M) and migration from closed (+/+) and open (Lp/Lp) neural tube (arrows in C,F,J,N). da, dorsal aorta. Scale bars: 500 µm in A,D; 200 µm in B,C,E,F; 250 µm in G,K; 100 µm in H-J,L-N.
Fig. 2. Vangl1 is not expressed in wild-type NC, nor ectopically in Vangl2Lp/Lp mutants. WISH in intact embryos shown from dorsal (A,E,I,M) and right lateral (A′,E′,I′,M′) views, and in sections (B-D,F-H,J-L,N-P) at levels indicated by dashed lines in A,E,I,M. Vangl1 mRNA expression is confined to midline neuroepithelium, from hindbrain to low trunk (arrows), in E8.5 wild-type embryos (+/+; A-D). There is no ectopic expression in Vangl2Lp/Lp embryos (Lp/Lp; E-H) nor overlap with Erbb3-positive NC (I-L). Vangl2 is expressed throughout the neuroepithelium (M-P), overlapping with Vangl1 only in midline cells, and not overlapping with Erbb3. Scale bars: 200 µm.
Fig. 3. Normal NC migration in Vangl1/2 double mutants and after acute Vangl2 downregulation in the NC lineage. (A-H) Control (A,C-E; Vangl1gt/+; Vangl2Δ/+) and double-mutant (B,F-H; Vangl1gt/gt; Vangl2Δ/Δ) embryos exhibit normal migration of Erbb3-positive cranial NC (E8.5; A,B) and cranial/trunk NC (E9.5; C-H). Acute NC downregulation of Vangl2 to test for a possible compensatory mechanism in Vangl2Lp/Lp embryos (I) reveals identical YFP-positive NC migration in control (J-L; Vangl2+/flox; Wnt1-Cre) and downregulation (M-O; Vangl2Lp/flox; Wnt1-Cre) E9.5 embryos. Arrows indicate comparable streams of NC cells migrating from the trunk neural tube in both genotypes. Scale bars: 200 µm in A; 500 µm in C,F; 100 µm in J-O.
Fig. 4. NC cells migrate similarly from Vangl2+/+ and Vangl2Lp/Lp explant cultures. YFP-positive NC are initially (0 h; A) on the dorsal margin of Vangl2+/+; Wnt1-Cre/YFP (+/+) explants and on Vangl2Lp/Lp; Wnt1-Cre/YFP (Lp/Lp) neural fold tips. Cells emerge in similar numbers (at 24 h; A), with no difference in outgrowth area (P=0.91, one-way ANOVA; B). Leading edge NC cells (anti-GFP/YFP; DAPI) are polarised (C, arrows) or non-polarised (C, arrowheads). Analysis of leading edge cells (D) reveals no difference between genotypes in the proportion of polarised cells nor in the mean distance migrated (P=0.42, E; P=0.21, F; one-way ANOVA). bf, bright field. Error bars indicate s.e.m. At least three explants were studied per genotype and time point. Scale bars: 200 µm in A; 50 µm in C.
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