XB-ART-55919
Front Physiol
January 1, 2019;
10
431.
Wolf-Hirschhorn Syndrome-Associated Genes Are Enriched in Motile Neural Crest Cells and Affect Craniofacial Development in Xenopus laevis.
Abstract
Wolf-Hirschhorn Syndrome (WHS) is a human developmental disorder arising from a hemizygous perturbation, typically a microdeletion, on the short arm of chromosome four. In addition to pronounced intellectual disability, seizures, and delayed growth, WHS presents with a characteristic facial dysmorphism and varying prevalence of microcephaly, micrognathia, cartilage malformation in the ear and nose, and facial asymmetries. These affected craniofacial tissues all derive from a shared embryonic precursor, the cranial neural crest (CNC), inviting the hypothesis that one or more WHS-affected genes may be critical regulators of neural crest development or migration. To explore this, we characterized expression of multiple genes within or immediately proximal to defined WHS critical regions, across the span of craniofacial development in the vertebrate model system Xenopus laevis. This subset of genes, whsc1, whsc2, letm1, and tacc3, are diverse in their currently-elucidated cellular functions; yet we find that their expression demonstrates shared tissue-specific enrichment within the anterior neural tube, migratory neural crest, and later craniofacial structures. We examine the ramifications of this by characterizing craniofacial development and neural crest migration following individual gene depletion. We observe that several WHS-associated genes significantly impact facial patterning, cartilage formation, neural crest motility in vivo and in vitro, and can separately contribute to forebrain scaling. Thus, we have determined that numerous genes within and surrounding the defined WHS critical regions potently impact craniofacial patterning, suggesting their role in WHS presentation may stem from essential functions during neural crest-derived tissue formation.
PubMed ID: 31031646
PMC ID: PMC6474402
Article link: Front Physiol
Grant support: [+]
R01 MH109651 NIMH NIH HHS, R03 DE025824 NIDCR NIH HHS
Species referenced: Xenopus laevis
Genes referenced: letm1 nelfa nsd2 tacc3 twist1
GO keywords: neural crest cell migration [+]
Morpholinos: letm1 MO1 nelfa MO1 nsd2 MO1 tacc3 MO2
Disease Ontology terms: Wolf-Hirschhorn syndrome [+]
Phenotypes: Xla Wt + letm1 MO (Fig. 3D, FGHI) [+]
Xla Wt + letm1 MO
(Fig. S4 J)
Xla Wt + nelfa MO (Fig. 3C, FGHI)
Xla Wt + nelfa MO (Fig. 4C, FGHI)
Xla Wt + nelfa MO (Fig. 7 DEF)
Xla Wt + nelfa MO (Fig. S4 F)
Xla Wt + nsd2 MO (Fig. 3B, FGHI)
Xla Wt + nsd2 MO (Fig. 5 B CDE)
Xla Wt + nsd2 MO (Fig. 6 B c2r2, D)
Xla Wt + nsd2 MO (Fig. 7 ABC)
Xla Wt + nsd2 MO (Fig. S4 B)
Xla Wt + tacc3 MO (Fig. 3E, FGHI)
Xla Wt + tacc3 MO (Fig. 4E, FGHI)
Xla Wt + tacc3 MO (Fig. 5 G HIJ)
Xla Wt + tacc3 MO (Fig. 7 JKL)
Xla Wt + tacc3 MO (Fig. S4 N)
Xla Wt + nelfa MO (Fig. 3C, FGHI)
Xla Wt + nelfa MO (Fig. 4C, FGHI)
Xla Wt + nelfa MO (Fig. 7 DEF)
Xla Wt + nelfa MO (Fig. S4 F)
Xla Wt + nsd2 MO (Fig. 3B, FGHI)
Xla Wt + nsd2 MO (Fig. 5 B CDE)
Xla Wt + nsd2 MO (Fig. 6 B c2r2, D)
Xla Wt + nsd2 MO (Fig. 7 ABC)
Xla Wt + nsd2 MO (Fig. S4 B)
Xla Wt + tacc3 MO (Fig. 3E, FGHI)
Xla Wt + tacc3 MO (Fig. 4E, FGHI)
Xla Wt + tacc3 MO (Fig. 5 G HIJ)
Xla Wt + tacc3 MO (Fig. 7 JKL)
Xla Wt + tacc3 MO (Fig. S4 N)
Article Images: [+] show captions
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FIGURE 1. WHS is typically caused by heterozygous microdeletion of numerous genes within 4p16.3. A segment of this region is illustrated here. A microdeletion that spans at least WHSC1, WHSC2, and LETM1 is currently assumed to be necessary for full WHS diagnostic presentation; children affected by the disorder often possess larger deletions that extend further telomeric and impact additional genes, such as TACC3. |
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FIGURE 2. WHS related genes are expressed in the migrating neural crest cells during embryonic development. (A,F) Lateral views of whole mount in situ hybridizations for twist, a CNC-enriched transcription factor. Arrows indicate the pharyngeal arches (PA). (B–E,G–J) In situ hybridizations for whsc1, whsc2, letm1, and tacc3 demonstrate enrichment in CNCs that occupy the PAs (n = 20 per probe, per timepoint). Scalebar is 250 μm. |
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FIGURE 3. WHS related gene depletion affects craniofacial morphology. (A–E) Frontal views of 3dpf embryos (st. 40) following WHS gene single KD. (F–I) Measurements for facial width, height, midface area, and midface angle. A significant 6.54% increase in facial width and 11.43% increase in midface area were observed for Whsc1 KD. Whsc2 KD caused a 12.01% reduction in facial width and a 6.79% reduction in midface area. Letm1 KD caused a 10.33% decrease in facial width and a 8.49% decrease in midface area. Tacc3 KD caused a 21.27% decrease in facial width and a 16.33% decrease in midface area, and an 8.27% decrease in midface angle. Significance determined using a student’s unpaired t-test. (Embryos quantified: Control = 137, Whsc1 KD = 100, Whsc2 KD = 185, Letm1 KD = 115, Tacc3 KD = 79.) ∗∗∗∗P < 0.0001, ∗∗∗P < 0.001, ∗∗P < 0.01, n.s., not significant. Scalebar = 250 μm. |
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FIGURE 4. Knockdown of Whsc2 and Tacc3 impact cartilage morphology. (A–E) Ventral view of 6dpf embryos following single WHS-assoc. gene KD, stained with Alcian Blue to label cartilage elements. (F–I) Measurements of the average area and width of the ceratohyal cartilage, total cartilage area, and width of the brachial arches. Neither Whsc1 nor Letm1 KD caused a significant change in any measured parameter. Whsc2 KD caused a 27.94% decrease in average area of the ceratohyal cartilage, and a 23.87% decrease in area of all craniofacial cartilage. Tacc3 KD caused a 48.5% decrease in the average area of the ceratohyal cartilage, a 24.03% decrease in total cartilage area, and a 28.58% decrease in ceratohyal cartilage width. Significance was determined using a student’s unpaired t-test. (Embryos quantified: Control = 17, Whsc1 KD = 41, Whsc2 KD = 39, Letm1 KD = 34, Tacc3 KD = 11.) ∗∗∗∗P < 0.0001, ∗∗∗P < 0.001, ∗P < 0.05, n.s., not significant. Scalebar is 250μm. |
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FIGURE 5. Knockdown of Whsc1 and Tacc3 decrease CNC migration in vivo. (A,B,F,G,K,L,P,Q) Anterior lateral views of tailbud stage embryos (depicted at st. 27), following whole mount in situ hybridization against twist. Each column of panels (A,B,F,G,K,L,Q) are lateral views of two sides of the same embryo. (C–E,H–J,M–O,R–T) Measurements were taken for the total area of the three PA (Arch 1-3 extend anterior to posterior), the length of each individual arch, and the migration distance, as measured from the dorsal most tip of each arch to the neural tube. Embryos were stained and quantified at stages 25–30. (K–T) Letm1 or Whsc2 KD did not significantly affect any of the measured parameters. (F–J) Tacc3 KD expression caused an 8.33% decrease in the total PA area, but did not affect length or arch migration. (A–E) Whsc1 KD caused a 23.57% decrease in PA area. Additionally, the length of the second and third pharyngeal arches decreased by 14.72 and 31.70%, respectively. The migration distance of the first, second and third pharyngeal arches decreased by 15.75, 24.04, and 29.29%, respectively. Significance determined using a student’s paired t-test. (Embryos quantified: Whsc1 KD = 13, Tacc3 KD = 18, Whsc2 KD = 12, Letm1 KD = 19.) ∗∗∗∗P < 0.0001, ∗∗∗P < 0.001, ∗P < 0.05, n.s., not significant. Scalebar is 250 μm. |
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FIGURE 6. Whsc1 manipulation alters CNC migration speeds in vitro. Dissected CNC explants from control, Whsc1 KD, or Whsc2 KD embryos were plated on fibronectin-coated coverslips, allowed to adhere and begin migration, and imaged for 3 h using 20× phase microscopy. (A) Representative explants at initial timepoint (0 min). (B) Explants after 3 h migration time. (C) Representative tracks generated by FiJi Trackmate plug-in. (D) Mean track speeds of Whsc1 or Whsc2 KD explants compared to their controls. (Explants quantified: 3–4 explants from control and KD embryos were plated for each experiment, explants with neural or epithelial contaminant were excluded from analysis. Three separate experiments were performed for each depletion. Whsc1 controls: 272 cells, 9 explants. Whsc1 KD: 282 cells, 9 explants. Whsc2 controls: 151 cells, 12 explants. Whsc2 KD: 195 cells, 8 explants.) ∗∗∗∗P < 0.0001, n.s., not significant. Scalebar is 250μm. |
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FIGURE 7. Whsc1, whsc2, and tacc3 facilitate normal forebrain development. (A,B,D,E,G,H,J,K) Dorsal view of X. laevis half-embryo gene depletions (6 days post-fertilization), following alpha-tubulin immunolabeling to highlight nervous system. (B,E,H,K) Dorsal view of embryos with superimposed outlines of forebrain and midbrain structures. Internal control is on left (white), depleted side is on right (dashed red). (Alpha-tubulin staining is bilateral; exogenous eGFP on KD side persisted in embryos shown, causing a unilaterally enriched green signal.) (C,F,I,L) Area of forebrain and midbrain. Whsc1 KD reduced forebrain area by 17.65%. Whsc2 KD reduced forebrain area by 17.33% and midbrain area by 4.14%. Letm1 KD caused no significant change in brain size. Tacc3 KD caused a 16.05% decrease in forebrain area. Significance determined using a student’s paired t-test. (Embryos quantified: Whsc1 KD = 14, Whsc2 KD = 18, Letm1 KD = 12, Tacc3 KD = 26.) ∗∗∗∗P < 0.0001, ∗∗∗P < 0.001, ∗P < 0.05, n.s., not significant. Scalebar is 250 μm. |
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FIGURE 8. Partial depletion of WHS-affected genes demonstrates numerous impacts on craniofacial development and neural crest migration. Tissues are denoted as affected (checked box) if phenotypes were significantly different from control (p ≤ 0.05); see individual figures for data distribution and statistics. (Abbreviations: PA, Pharyngeal Arch) ∗Denotes pre-migratory CNC (st. 16). |
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FIGURE S1 | Expression patterns for WHS related genes across early development. In situ hybridization utilized (A–F) antisense mRNA probe to whsc1, (G–L) full-length antisense mRNA probe to whsc2, (M–R) full-length antisense mRNA probe to letm1, and (S-X) 1 kb partial-length antisense mRNA probe to tacc3. Embryos shown at blastula stage (A,G,M,S), in dorsal view at stage 16–20 (B,H,N,T), in lateral view at stage 20–25 (C,I,O,U), detail of lateral anterior region at stage 35 (D,J,P,V), and in both lateral and dorsal views from stages 39–42 (E,K,Q,W and F,L,R,X). (Y) In situ hybridization probes generated against sense strands of WHS gene mRNAs, shown at stage 25. Brown coloration (S,T) is unbleached pigment, unrelated to in situ hybridization staining. Scalebar is 250 μm.bryos were anesthetized with benzocaine. |
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FIGURE S2 | Validation of WHS related MOs. (A,B) Gel of polymerase chain reaction (PCR) that shows injection of 10 ng MO targeted to whsc1 mRNA causes a greater than 80% reduction at 2 dpf. (C,D) Injection of 20 ng of a MO targeted against letm1 causes an 55% decrease in letm1 mRNA 2 dpf. (E,F) Western blot showing 10 ng injection of a MO targeted against whsc2 results in a greater than 50% reduction in Whsc2 protein by 2 dpf. (G,H) Western blot showing 40 ng of a MO targeted against tacc3 results in 22% reduction. Bar graphs (B,D,F,H) depict densitometry of gels (A,C) or blot (E,G) shown, but is consistent across triplicate results. |
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FIGURE S3 | Demonstration of measurement schemes for craniofacial morphology. Measurements for Figure 3 and Supplementary Figure S4 were performed as indicated. (A) Facial width was measured from the center of each eye. (B) Facial height was determined at the midline, from the top of the cement gland to the top of the eyes. (C) Midface angle was measured from the top of the cement gland to the center of each eye. (D) Facial area was measured as the space encapsulated within the perimeter of each eye. Adapted from Kennedy and Dickinson (2014). |
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FIGURE S4 | Craniofacial defects caused by WHS-associated gene KD are rescued by co-injection of exogenous mRNA co-expression. Facial widths from control, depletion, or rescue strategies were measured in tadpoles (st. 40). Row 1: Embryos injected with (A) control MO (n = 17), (B) 10 ng whsc1 MO (n = 14), or (C) 10 ng of whsc1 MO and 250 pg of whsc1 exogenous mRNA. (D) Comparisons of facial width showed an 8.76% increase in facial width with Whsc1 KD, which was rescued by whsc1 mRNA co-injection. Row 2: Embryos injected with (E) control MO (n = 21), (F) 10 ng whsc2 MO (n = 17), or (G) both 10ng of whsc2 MO and 250 pg of whsc2 mRNA (n = 19). (H) Whsc2 knockdown caused an 8.37% reduction in facial width, which was rescued by exogenous whsc2 mRNA co-injection. Row 3: Embryos injected with (I) control MO (n = 10), (J) 20 ng of letm1 MO, or (K) 20 ng letm1 MO and 1500 pg of letm1 mRNA (n = 11). (L) KD of Letm1 caused a 14.95% decrease in facial width, and was rescued by co-injection of exogenous letm1 mRNA. Row 4: Embryos injected with (M) control MO (n = 9), (N) 20 ng of tacc3 MO (n = 18), or O) 20 ng of tacc3 morpholino and 1000 pg of tacc3 mRNA (n = 16). (P) Tacc3 KD resulted in a 9.01% decrease in facial width, and was rescued by tacc3 mRNA co-injection. Significance determined using a student’s unpaired t-test. ∗∗P < 0.01, ∗P < 0.05, n.s., not significant. Scalebar is 250μm. |
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FIGURE S5 | Half embryo knockdown can be utilized for analysis of brain morphology and neural crest cell migration in vivo. (A) At the 2-cell stage, a single blastomere is injected with WHS-associated gene MOs and exogenous eGFP mRNA. After neurulation (approx. stage 21), embryos are sorted based on left or right eGFP fluorescence, to determine side of depletion. To examine neural crest cell size, migration and morphology embryos were fixed between stage 25–30, and in situ hybridization was performed using twist anti-sense probe. To characterize brain morphology, embryos were raised to st. 47, and fixed and labeled with alpha-tubulin antibody, a neuronal marker, and Alexa-488 secondary. (B–D) Control MO does not significantly impact brain size, compared to non-injected hemispheres (a paired internal control). |
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Erdogan, The microtubule plus-end-tracking protein TACC3 promotes persistent axon outgrowth and mediates responses to axon guidance signals during development. 2018, Pubmed , Xenbase
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Gergely, The TACC domain identifies a family of centrosomal proteins that can interact with microtubules. 2001, Pubmed
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Griffin, RAPGEF5 Regulates Nuclear Translocation of β-Catenin. 2018, Pubmed , Xenbase
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Hammond, Fine-grained facial phenotype-genotype analysis in Wolf-Hirschhorn syndrome. 2012, Pubmed
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Huang, PINK1-mediated phosphorylation of LETM1 regulates mitochondrial calcium transport and protects neurons against mitochondrial stress. 2018, Pubmed
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