XB-ART-58916
Front Cell Dev Biol
2022 Jan 01;10:844619. doi: 10.3389/fcell.2022.844619.
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Reduced Retinoic Acid Signaling During Gastrulation Induces Developmental Microcephaly.
Gur M
,
Bendelac-Kapon L
,
Shabtai Y
,
Pillemer G
,
Fainsod A
.
???displayArticle.abstract???
Retinoic acid (RA) is a central signaling molecule regulating multiple developmental decisions during embryogenesis. Excess RA induces head malformations, primarily by expansion of posterior brain structures at the expense of anterior head regions, i.e., hindbrain expansion. Despite this extensively studied RA teratogenic effect, a number of syndromes exhibiting microcephaly, such as DiGeorge, Vitamin A Deficiency, Fetal Alcohol Syndrome, and others, have been attributed to reduced RA signaling. This causative link suggests a requirement for RA signaling during normal head development in all these syndromes. To characterize this novel RA function, we studied the involvement of RA in the early events leading to head formation in Xenopus embryos. This effect was mapped to the earliest RA biosynthesis in the embryo within the gastrula Spemann-Mangold organizer. Head malformations were observed when reduced RA signaling was induced in the endogenous Spemann-Mangold organizer and in the ectopic organizer of twinned embryos. Two embryonic retinaldehyde dehydrogenases, ALDH1A2 (RALDH2) and ALDH1A3 (RALDH3) are initially expressed in the organizer and subsequently mark the trunk and the migrating leading edge mesendoderm, respectively. Gene-specific knockdowns and CRISPR/Cas9 targeting show that RALDH3 is a key enzyme involved in RA production required for head formation. These observations indicate that in addition to the teratogenic effect of excess RA on head development, RA signaling also has a positive and required regulatory role in the early formation of the head during gastrula stages. These results identify a novel RA activity that concurs with its proposed reduction in syndromes exhibiting microcephaly.
???displayArticle.pubmedLink??? 35372345
???displayArticle.link??? Front Cell Dev Biol
Species referenced: Xenopus laevis
Genes referenced: admp aldh1a1 aldh1a2 aldh1a3 bmp4 cer1 chrd chrd.2 cyp26a1 dhrs3 dkk1 frzb gsc hoxa1 hoxb1 hoxb4 muc2 myod1 ncam1 otx2 pax6 rdh10 smad6 szl ventx1 ventx1.2 wnt8a
GO keywords: retinoic acid binding [+]
vitamin A metabolic process
retinoic acid receptor signaling pathway
brain morphogenesis
CRISPR-cas system
???displayArticle.morpholinos??? aldh1a2 MO2 aldh1a3 MO1
gRNAs referenced: aldh1a2 gRNA1 aldh1a3 gRNA1
???displayArticle.disOnts??? fetal alcohol syndrome [+]
Phenotypes: Xla Wt + DEAB (Fig.1.D) [+]
Xla Wt + DEAB
(Fig.1.H)
Xla Wt + DEAB (Fig.2.A)
Xla Wt + DEAB (Fig.3.A-G)
Xla Wt + DEAB (Fig.3.H)
Xla Wt + Retinoic acid (Fig.3.A-G)
Xla Wt + Retinoic acid (Fig.7)
Xla Wt + Retinoic acid (Fig.7.A)
Xla Wt + Retinoic acid (Fig.7.A)
Xla Wt + Retinoic acid (Fig.7.C)
Xla Wt + aldh1a2 CRISPR (Fig.7.B)
Xla Wt + aldh1a2 CRISPR (Fig.7.C)
Xla Wt + aldh1a3 CRISPR (Fig.7.B)
Xla Wt + bmp4 (Fig.4.I)
Xla Wt + bmp4 (Fig.4.I)
Xla Wt + bmp4 (Fig.4.I)
Xla Wt + cyp26a1 (Fig.1.B,D)
Xla Wt + cyp26a1 (Fig.1.C,D)
Xla Wt + cyp26a1 + DEAB (Fig.1.D)
Xla Wt + cyp26a1 + DEAB (Fig.1.D)
Xla Wt + cyp26a1 + aldh1a2 MO (Fig.5.B,E)
Xla Wt + cyp26a1 + aldh1a3 MO (Fig.5.B,F)
Xla Wt + cyp26a1 + aldh1a3 MO (Fig.7)
Xla Wt + smad6 (Fig.S1.B,E)
Xla Wt + wnt8a (Fig.1.F,H)
Xla Wt + wnt8a (Fig.4.H)
Xla Wt + wnt8a (Fig.4.H)
Xla Wt + wnt8a (Fig.4.H)
Xla Wt + wnt8a (Fig.5.G)
Xla Wt + wnt8a (Fig.6.A,D)
Xla Wt + wnt8a (Fig.S1.A,D)
Xla Wt + {dn}bmpr1a (Fig.S1.F)
Xla Wt + DEAB (Fig.2.A)
Xla Wt + DEAB (Fig.3.A-G)
Xla Wt + DEAB (Fig.3.H)
Xla Wt + Retinoic acid (Fig.3.A-G)
Xla Wt + Retinoic acid (Fig.7)
Xla Wt + Retinoic acid (Fig.7.A)
Xla Wt + Retinoic acid (Fig.7.A)
Xla Wt + Retinoic acid (Fig.7.C)
Xla Wt + aldh1a2 CRISPR (Fig.7.B)
Xla Wt + aldh1a2 CRISPR (Fig.7.C)
Xla Wt + aldh1a3 CRISPR (Fig.7.B)
Xla Wt + bmp4 (Fig.4.I)
Xla Wt + bmp4 (Fig.4.I)
Xla Wt + bmp4 (Fig.4.I)
Xla Wt + cyp26a1 (Fig.1.B,D)
Xla Wt + cyp26a1 (Fig.1.C,D)
Xla Wt + cyp26a1 + DEAB (Fig.1.D)
Xla Wt + cyp26a1 + DEAB (Fig.1.D)
Xla Wt + cyp26a1 + aldh1a2 MO (Fig.5.B,E)
Xla Wt + cyp26a1 + aldh1a3 MO (Fig.5.B,F)
Xla Wt + cyp26a1 + aldh1a3 MO (Fig.7)
Xla Wt + smad6 (Fig.S1.B,E)
Xla Wt + wnt8a (Fig.1.F,H)
Xla Wt + wnt8a (Fig.4.H)
Xla Wt + wnt8a (Fig.4.H)
Xla Wt + wnt8a (Fig.4.H)
Xla Wt + wnt8a (Fig.5.G)
Xla Wt + wnt8a (Fig.6.A,D)
Xla Wt + wnt8a (Fig.S1.A,D)
Xla Wt + {dn}bmpr1a (Fig.S1.F)
???attribute.lit??? ???displayArticles.show???
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FIGURE 1. Retinoic acid is required for normal head development. Embryos were injected with RNA encoding CYP26A1 and treated with DEAB to reduce the endogenous levels of RA. (A) Control embryo (st. 30) processed for in situ hybridization with pax6 (eyes, pink) and muc2 (cement gland, purple) specific probes. (B) Embryo injected dorsally with cyp26a1 RNA exhibiting mild microcephaly. Turquoise staining is the LacZ lineage tracer. (C) Severe microcephaly in an embryo injected with cyp26a1 mRNA in the dorsal region. (D) Frequency of microcephaly induction by combined RA knockdown in embryos injected dorsally or ventrally with cyp26a1 RNA and treated with DEAB. (E) Control st. 14/15 embryo processed for in situ hybridization with pax6 (eyes) and ncam (neural plate). (F) Embryo ventrally injected with wnt8a RNA to induce a secondary axis analyzed for eye and neural plate formation. (G) Loss of anterior head structures (eyes, pax6) in the induced secondary axis by co-injection of cyp26a1 RNA with the wnt8 mRNA. The primary and secondary axes are labeled (1st, 2nd). (H) Inhibition of anterior head formation in twinned embryos induced by ventral wnt8a injection or parallel inhibition of BMP (tALK3) and Wnt (DKK1) signaling and reduction of RA levels (DEAB treatment or CYP26A1 overexpression). The overall number of embryos injected or manipulated is shown (n =). *, p < 0.05; **, p < 0.01; ****, 0.0001; ns, not significant. |
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FIGURE 2. RA function is required during the early gastrula stages for normal anterior head development. (A) Embryos were treated with DEAB starting at different developmental stages and analyzed for the effect on head development during tailbud stages (st. 32). (B) Untreated embryos were injected with the RA reporter plasmid, RAREZ. At different gastrula stages, groups of embryos (5) were collected and processed for chemiluminescent analysis of the ß-galactosidase activity. Samples were normalized to the st. 10 sample. *, p < 0.05 **, p < 0.01; ****, p < 0.0001; ns, not significant. |
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FIGURE 3. Positive and negative regulation of organizer genes by RA. (A–G) Embryos were treated with increasing concentrations of atRA (10 nM–10 μM) or DEAB (30–250 μM) from late blastula to early gastrula. Expression changes of hoxb1 (A), cyp26a1 (B), chrd.1 (C), admp (D), dkk1 (E), cer1 (F), and otx2 (G) were studied by qPCR. Samples were normalized to control expression levels (gray bar). (H) Fine titration of RA biosynthesis inhibition using DEAB (1–30 μM). Expression changes were determined for gsc, cyp26a1, chrd.1, admp, dkk1, cer1, and otx2 by qPCR. |
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FIGURE 4. Expression of aldh1a3 in the migrating LEM/PCM cells. (A) Mid-gastrula embryos (st. 11) were dissected into dorsal, lateral, and ventral regions, and RNA was extracted from each region. The relative abundance of aldh1a1, aldh1a2, and aldh1a3 was studied by qPCR. The accuracy of the dissections was determined by qPCR of chrd.1, myod1, and szl as dorsal, lateral, and ventral markers, respectively. In comparison to the szl transcript distribution, all other genes had a significantly different distribution, p < 0.0001 using the Fisher exact probability test. Spatial expression pattern comparison between aldh1a3 and aldh1a2 (B,C), aldh1a3 and cyp26a1 (D,E), and aldh1a3 and otx2 (F,G). (B–D,F,G) dorsal view, anterior to the top. (H,I) Embryos were injected with mRNA encoding WNT8a (H) or BMP4 (I) and samples were collected during early and mid-gastrula, and early neurula stages (st. 10.5, 11, and 13). qPCR analysis was performed for aldh1a2 and aldh1a3, the dorsal markers gsc and admp, and the ventral genes szl and ventx1.2. Relative expression was normalized to levels in control embryos. Groups of injected embryos were incubated to tailbud stages to determine their dorsoanterior index (DAI) (Kao and Elinson, 1988). wnt8a, DAI = 5.67; bmp4, DAI = 3.64. |
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FIGURE 5. ALDH1A3 is necessary for normal head development. Embryos were injected with the R2MO or R3MO to reduce the activity of ALDH1A2 or ALDH1A3, respectively. (A) Analysis of the effect on the RA signaling level by co-injection of the RA reporter plasmid and chemiluminescent analysis of the ß-galactosidase activity. (B–F) Embryos injected dorsally with the R2MO, R3MO, or coMO to induce ALDH1A2 or ALDH1A3 knockdown in the Spemann-Mangold organizer. Embryos were sensitized for changes in RA levels by co-injection of low, non-teratogenic, amounts of cyp26a1 RNA. The extent of microcephaly induction was quantitated (B). Examples of head development for control uninjected (C), coMO (D), R2MO (E), and R3MO (F) injected embryos are shown. (G–J) Analysis of head malformations in secondary axes induced by ventral injection of wnt8a RNA together with ALDH1A2 or ALDH1A3 knockdown. (G) Control embryo. (H) ALDH1A2 knockdown. (I) ALDH1A3 knockdown. (J) Quantitation of the effect of ALDH1A2 or ALDH1A3 knockdown on head development in the induced secondary axes. The overall number of embryos injected or manipulated is shown (n =). *, p < 0.05 **, p < 0.01; ***, p < 0.001 ****, p < 0.0001; ns, not significant. |
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FIGURE 6. aldh1a3 CRISPants exhibit enhanced head malformations. Secondary axes were induced by ventrally injecting wnt8a mRNA. Co-injection of sgR2 or sgR3 RNPs was performed to generate aldh1a2 or aldh1a3 CRISPant embryos, respectively. (A) Secondary axis induction efficiency in wnt8a RNA injected embryos along or in conjunction with aldh1a2 or aldh1a3 CRISPant induction. (B) Control embryo. (C) aldh1a2 CRISPant embryo with two axes. (D) aldh1a3 CRISPant twinned axis embryo. (E) Analysis of the effect of the aldh1a2 and aldh1a3 CRISPR/Cas9-mediated knockdown on head formation in the induced secondary axes. The overall number of embryos injected or manipulated is shown (n =). Percent embryos wnt8a mRNA injected, embryos with secondary axes without heads and with heads. **, p < 0.01; ns, not significant. |
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FIGURE 7. RA rescues the microcephaly induced by loss of ALDH1A3 activity. Microcephaly was induced in Xenopus embryos by targeting the aldh1a3 gene with CRISPR/Cas9+sgR3. As controls, embryos were injected with Cas9 only. For rescue of the microcephalic phenotype, embryos were treated with 5 nM or 10 nM RA. The rescue efficiency was calculated by Chi-square, comparing each treatment to the Cas9 control microcephaly level. *, p < 0.05; **, p < 0.01; ****, p < 0.0001; ns, not significant. |
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FIGURE 8. RA autoregulation and control of LEM/PCM gene expression. (A) Embryos were treated with RA (100 nM) during late blastula stages and RNA samples were collected during early (st. 10.25) and late (st. 12) gastrula stages. The effect of the manipulation on RA network gene expression (dhrs3, cyp26a1, aldh1a2, aldh1a3, and rdh10) was determined by qPCR. The expression of hoxb1 was studied to monitor the changes in RA level. Samples were normalized to control expression level at each stage. (B,C) The expression of organizer genes linked to head formation (gsc, cer1, dkk1, frzb1, admp, otx2, and chrd.1) was analyzed in aldh1a2 and aldh1a3 CRISPants. The RA-regulated genes, cyp26a1, hoxa1, hoxb4, aldh1a2, and aldh1a3, were studied in parallel. The gene expression analysis was performed at st. 10.25 (B) and st. 12 (C). Relative expression was normalized to control expression levels at each stage. *, p < 0.05; **, p < 0.01; ***, p < 0.001; ****, p < 0.0001; ns, not significant. |
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FIGURE 9. RA biosynthetic/signaling centers during gastrulation. (A) Schematic depiction of an early gastrula embryo where the domain of overlapping aldh1a2 and aldh1a3 expression in the Spemann-Mangold organizer is marked (green box). The RA producing and regulatory activities are summarized. (B) Schematic summary of the two RA biosynthetic/signaling centers during late gastrula. The domains of expression and activity of aldh1a2 in the trunk (blue) and aldh1a3 in the LEM/PCM (purple) are shown. |
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