XB-ART-55848
Dev Biol
2019 Feb 01;4461:68-79. doi: 10.1016/j.ydbio.2018.12.003.
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Six1 and Irx1 have reciprocal interactions during cranial placode and otic vesicle formation.
Sullivan CH
,
Majumdar HD
,
Neilson KM
,
Moody SA
.
???displayArticle.abstract???
The specialized sensory organs of the vertebrate head are derived from thickened patches of cells in the ectoderm called cranial sensory placodes. The developmental program that generates these placodes and the genes that are expressed during the process have been studied extensively in a number of animals, yet very little is known about how these genes regulate one another. We previously found via a microarray screen that Six1, a known transcriptional regulator of cranial placode fate, up-regulates Irx1 in ectodermal explants. In this study, we investigated the transcriptional relationship between Six1 and Irx1 and found that they reciprocally regulate each other throughout cranial placode and otic vesicle formation. Although Irx1 expression precedes that of Six1 in the neural border zone, its continued and appropriately patterned expression in the pre-placodal region (PPR) and otic vesicle requires Six1. At early PPR stages, Six1 expands the Irx1 domain, but this activity subsides over time and changes to a predominantly repressive effect. Likewise, Irx1 initially expands Six1 expression in the PPR, but later represses it. We also found that Irx1 and Sox11, a known direct target of Six1, reciprocally affect each other. This work demonstrates that the interactions between Six1 and Irx1 are continuous during PPR and placode development and their transcriptional effects on one another change over developmental time.
???displayArticle.pubmedLink??? 30529252
???displayArticle.pmcLink??? PMC6349505
???displayArticle.link??? Dev Biol
???displayArticle.grants??? [+]
R01 DE022065 NIDCR NIH HHS, R01 DE026434 NIDCR NIH HHS, U54 HD090257 NICHD NIH HHS
Species referenced: Xenopus laevis
Genes referenced: cdknx ctrl eya1 fgf8 foxd3 irx1 myc neurod1 pax2 pax3 six1 sox11 sox2 sox3 sox9 tfap2a tubb2b tubb4b zic1 zic2 znrd2
GO keywords: otic placode formation [+]
???displayArticle.morpholinos??? six1 MO1 six1 MO2 sox11 MO2 Sox11 MO3
Phenotypes: Xla Wt + irx1 (Fig. 10 A col 1) [+]
Xla Wt + irx1
(Fig. 10 A col 2)
Xla Wt + irx1 (Fig. 10 B col 1)
Xla Wt + irx1 (Fig. 10 B col 2)
Xla Wt + irx1 (Fig. 10 C Col 1)
Xla Wt + irx1 (Fig. 10 C col 2)
Xla Wt + irx1 (Fig. 10 C col 3)
Xla Wt + irx1 (Fig. 6 A)
Xla Wt + irx1 (Fig. 6 B)
Xla Wt + irx1 (Fig. 6 D)
Xla Wt + irx1 (Fig. 6 D)
Xla Wt + irx1 (Fig. 7 A)
Xla Wt + irx1 (Fig. 7 C)
Xla Wt + irx1 (Fig. 8 A)
Xla Wt + irx1 (Fig. 8 B)
Xla Wt + irx1 (Fig. 8 C)
Xla Wt + irx1 (Fig. 8 D)
Xla Wt + irx1 (Fig. 8 E,F)
Xla Wt + irx1 (Fig. 8 G,H,I)
Xla Wt + irx1 (Fig. 9 C)
Xla Wt + irx1 (Fig 9 A. col. 1)
Xla Wt + irx1 (Fig. 9 A col. 2)
Xla Wt + irx1 + Six1 MO (Fig. 10 col 3)
Xla Wt + irx1 + Six1 MO (Fig. 10 D col 1)
Xla Wt + irx1 + Six1 MO (Fig. 10 D col 2)
Xla Wt + irx1-VP16 (Fig. 5 A)
Xla Wt + irx1-VP16 (Fig. 5 B)
Xla Wt + irx1-VP16 (Fig. 5 C)
Xla Wt + irx1-VP16 (Fig. 5 D)
Xla Wt + six1 (Fig.3 A,B)
Xla Wt + six1 (Fig. 3 E,F)
Xla Wt + six1 (Fig, 3G, col.1)
Xla Wt + six1 (fig. 3 G, col. 2)
Xla Wt + six1 (Fig. 9 F col 1)
Xla Wt + six1 (Fig. 9 F col 2)
Xla Wt + six1-EnR (Fig. 3 C,F)
Xla Wt + six1 + eya1 (Fig. 3 A,B)
Xla Wt + six1 + eya1 (Fig. 3 E,F)
Xla Wt + six1-GR + Dex (16) (Fig. 4)
Xla Wt + six1-GR + Dex (16) (Fig. 9 H)
Xla Wt + six1-GR + Dex (18) (Fig. 4)
Xla Wt + six1 MO (Fig. 2A)
Xla Wt + six1 MO (Fig.2B)
Xla Wt + six1 MO (Fig. 2C. col.2)
Xla Wt + six1-VP16 (Fig. 3 D)
Xla Wt + Sox11 (Fig. 9 J)
Xla Wt + Sox11 (Fig. 9 K)
Xla Wt + Sox11 MO (Fig. 9 I)
Xla Wt + Tg(irx1-EnR-hGR) + ChX + Dex (Fig. 9 E)
Xtr Wt + six1 CRISPR (Fig. S1 D col 2)
Xla Wt + irx1 (Fig. 10 B col 1)
Xla Wt + irx1 (Fig. 10 B col 2)
Xla Wt + irx1 (Fig. 10 C Col 1)
Xla Wt + irx1 (Fig. 10 C col 2)
Xla Wt + irx1 (Fig. 10 C col 3)
Xla Wt + irx1 (Fig. 6 A)
Xla Wt + irx1 (Fig. 6 B)
Xla Wt + irx1 (Fig. 6 D)
Xla Wt + irx1 (Fig. 6 D)
Xla Wt + irx1 (Fig. 7 A)
Xla Wt + irx1 (Fig. 7 C)
Xla Wt + irx1 (Fig. 8 A)
Xla Wt + irx1 (Fig. 8 B)
Xla Wt + irx1 (Fig. 8 C)
Xla Wt + irx1 (Fig. 8 D)
Xla Wt + irx1 (Fig. 8 E,F)
Xla Wt + irx1 (Fig. 8 G,H,I)
Xla Wt + irx1 (Fig. 9 C)
Xla Wt + irx1 (Fig 9 A. col. 1)
Xla Wt + irx1 (Fig. 9 A col. 2)
Xla Wt + irx1 + Six1 MO (Fig. 10 col 3)
Xla Wt + irx1 + Six1 MO (Fig. 10 D col 1)
Xla Wt + irx1 + Six1 MO (Fig. 10 D col 2)
Xla Wt + irx1-VP16 (Fig. 5 A)
Xla Wt + irx1-VP16 (Fig. 5 B)
Xla Wt + irx1-VP16 (Fig. 5 C)
Xla Wt + irx1-VP16 (Fig. 5 D)
Xla Wt + six1 (Fig.3 A,B)
Xla Wt + six1 (Fig. 3 E,F)
Xla Wt + six1 (Fig, 3G, col.1)
Xla Wt + six1 (fig. 3 G, col. 2)
Xla Wt + six1 (Fig. 9 F col 1)
Xla Wt + six1 (Fig. 9 F col 2)
Xla Wt + six1-EnR (Fig. 3 C,F)
Xla Wt + six1 + eya1 (Fig. 3 A,B)
Xla Wt + six1 + eya1 (Fig. 3 E,F)
Xla Wt + six1-GR + Dex (16) (Fig. 4)
Xla Wt + six1-GR + Dex (16) (Fig. 9 H)
Xla Wt + six1-GR + Dex (18) (Fig. 4)
Xla Wt + six1 MO (Fig. 2A)
Xla Wt + six1 MO (Fig.2B)
Xla Wt + six1 MO (Fig. 2C. col.2)
Xla Wt + six1-VP16 (Fig. 3 D)
Xla Wt + Sox11 (Fig. 9 J)
Xla Wt + Sox11 (Fig. 9 K)
Xla Wt + Sox11 MO (Fig. 9 I)
Xla Wt + Tg(irx1-EnR-hGR) + ChX + Dex (Fig. 9 E)
Xtr Wt + six1 CRISPR (Fig. S1 D col 2)
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Fig. 1. Animal pole view of a 16-cell stage embryo with dorsal to the top. Nomenclature on the left side indicates blastomere names according to Hirose and Jacobson (1979). |
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Fig. 2. Six1 is required for Irx1 expression in the PPR and otic vesicle. (A) Irx1 expression in the PPR (black arrows) is distinct on the control side (ctrl) but not detected on the MO-mediated knock-down (KD) side (red arrows). np, neural plate. (B) Irx1 expression in two placodes is smaller and fainter on the KD side (red arrows) compared to the control side (black arrows). nt, neural tube. (C) Irx1 expression in the control otic vesicle (left image) forms two distinct patches (black arrows), whereas the anterior patch often is undetectable on the KD side (red arrows). e, eye. A, B, anterior views; C, side views, all with dorsal to the top. Percentages are the frequencies of the phenotypes; numbers in parentheses are the sample sizes. |
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Fig. 3. Increasing Six1 levels represses Irx1 expression. (A) Six1 or Six1+Eya1 mRNAs (right sides) reduce the size of the Irx1 expression domain in the PPR or placodes. Black arrows denote Irx1 PPR/placode expression on the control side; red arrows denote the same on the injected side, which also is indicated by the pink βGal lineage tracer. np, neural plate; nt, neural tube. (B) The percentage of embryos showing the same Irx1 phenotypes as in (A). *, indicates a significant increase (p < 0.05) in frequency comparing 800 pg to either 200 pg or 400 pg of Six1 mRNA. Co-expressing Six1 +Eya1 mRNAs does not significantly alter the frequency of the phenotype (p > 0.05). There were no significant differences between Six1 or Six1 +Eya1 mRNAs. Numbers above bars indicate the sample size. (C) The Six1 repressive construct (Six1EnR, 400 pg) also reduces Irx1 PPR expression (red arrow). (D) The Six1 activating construct (Six1VP16, 400 pg) broadens the Irx1 PPR domain (red arrow), as indicated by the red bar (compare to control width, black bar). (E) Six1 and Six1 +Eya1 mRNAs reduce Irx1 expression in the otic vesicle. Black arrows denote otic vesicle on control side, and red arrows denote it on injected side of same embryo. (F) The percentage of embryos that show the same phenotype as in (E) when injected with Six1, Six1 +Eya1 or Six1EnR mRNA. Numbers above bars indicate the sample size. There are no significant differences (p > 0.05) across the groups. (G) Six1 also reduces Sox9 and Pax2 expression in the otic vesicle. Black arrows denote otic vesicle on control side, and red arrows denote it on injected side of same embryo. A, C, D are anterior views, E, G are side views, all with dorsal to the top. |
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Fig. 4. Early activation of Six1 broadens Irx1 PPR expression, whereas later activation reduces it. Embryos were injected with Six1-hGR mRNA (400 pg) and treated with Dexamethasone (Dex) at indicated stages. Those treated at st 14 or 16 were fixed at st 18–19 to analyze Irx1 PPR/placode expression. Those treated at st 18 were fixed at st 24–28 to analyze Irx1 otic expression. Each bar indicates the percentage of embryos in which Irx1 expression was either broader compared to control side (blue), reduced compared to control side (orange), or the same as control side (no change, NC, grey) of the same embryo. The data for injected embryos that were not exposed to Dex and fixed at st 18/19 are shown in the left-most bar (no Dex) to indicate the background leakiness of the construct. Each experimental group was significantly different from the no Dex group, and significantly different from each other (p < 0.05). Control, uninjected embryos treated with Dex rarely showed an asymmetry in Irx1 expression (Dex st 14: 7.7%, n = 52; Dex st 16: 5.3%, n = 19; Dex st 18: 4.8%, n = 21). |
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Fig. 5. Irx1 is required for PPR and otic gene expression (A) Injecting a dominant-negative Irx1 construct (DN-Irx1) results in loss of Six1 PPR expression (red arrows) in every embryo. Black arrows denote normal expression on control (ctrl) side. (B) Injecting DN-Irx1 results in loss of Sox11 PPR expression (red arrows) in every embryo. Black arrows denote normal expression on control side. (C) Injecting DN-Irx1 results in loss of Six1 otic expression (red arrow) in every embryo. Black arrow denotes normal expression on control side. (D) Injecting DN-Irx1 results in loss of Pax2 otic expression (red arrow) in every embryo. Black arrow denotes normal expression on control side. A, B are anterior views; C, D are side views, all with dorsal to the top. np, neural plate; e, eye. |
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Fig. 6. Increased Irx1 reduces PPR and otic gene expression. (A) Increasing Irx1 by mRNA injection (right side) reduced the size of the Six1 expression domain in the PPR. Black arrows denote Six1 expression on the control side; red arrow denotes the reduced domain on the injected side. (B) Increased Irx1 reduced the size of the Eya1 expression domain in the PPR. (C) The percentage of embryos that showed the same phenotype as in A and B when injected with Irx1 mRNA. Irx1–800 pg caused the Six1 phenotype significantly more frequently (*, p < 0.05) than Irx1–200 pg. There were no significant differences across Irx1 mRNA doses for Eya1 (p > 0.05). Numbers above the bars indicate sample size. (D) Increased Irx1 reduced the size of the Sox9 and Pax2 domains in the otic vesicle (red arrows) compared to control side of same embryo (black arrows). (E) Embryos were injected with Irx1-EnR-hGR mRNA (400 pg) and treated with Dexamethasone (Dex) at indicated stages. Analyses of Six1 expression were performed as described in Fig. 4. Each experimental group was significantly different from the no Dex group, and significantly different from each other (p < 0.05). Control, uninjected embryos treated with Dex did not show an asymmetry in Six1 expression (Dex st 14: 0%, n = 25; Dex st 16: 0%, n = 15; Dex st 18: 0%, n = 25). A, B are anterior views; D are side views, all with dorsal to the top. |
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Fig. 7. Irx1 may affect PPR gene expression by downregulating Fgf. (A) When Irx1 mRNA (400 pg) was injected into animal blastomeres, an open blastopore phenotype (arrows) was observed at closed neural tube stages. Dorsal view, anterior (a) to the top, posterior (p) to the bottom. (B) The frequency of this phenotype depended upon the cell injected (see Fig. 1 for blastomere nomenclature). (C) Irx1 mRNA (400 pg) injection reduced the size of the Fgf8 expression domain in the PPR. Black arrows denote Fgf8 expression in the PPR on the control side; red arrows denote the reduced domain on the injected side. (D) In the majority of embryos co-injected with Irx1 plus cFgfr1 mRNAs, Six1 expression was restored (76.7%, n = 60). Black arrows denote control side; red arrows denote injected side. C, D are anterior views, dorsal to the top. |
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Fig. 8. Increased Irx1 alters BZ and NC gene expression. (A) Increased Irx1 expands the width of the Pax3 domain (red bar) compared to control side (black bar). (B) Increased Irx1 expands the width of the Zic1 neural crest domain (red bar) compared to control side (black bar). (C) Increased Irx1 expands the width of the Zic2 neural crest domain (red bar) compared to control side (black bar). (D) Increased Irx1 extends the anterior-posterior extent of the Tfap2α neural crest domain (between red arrows) compared to control side (between black arrows). (E) Increased Irx1 either expands (left embryo) or reduces (right embryo) the Foxd3 domain. inj, injected side; ctrl, control side. (F) Percentages of embryos showing reduced (orange), expanded (blue) or no change (NC, grey) of Foxd3 domains after injection of different doses of Irx1 mRNA. The frequencies of the Foxd3 phenotypes were not significantly different between 200 pg and 400 pg, but 800 pg caused reduction of Foxd3 at a significantly higher frequency (*, p < 0.05). (G) Increased Irx1 reduced the Sox9 neural crest domain (red arrows) compared to control side (black arrows). It also reduced the size of the Sox9-expressing otic placode (outlined in green). (H) Percentages of embryos showing reduced (orange), expanded (blue) or no change (NC, grey) in Sox9 neural crest (NC) domains after injection of different doses of Irx1 mRNA. These phenotypes were not significantly different across the doses (p > 0.05). (I) Percentages of embryos showing reduced (orange), expanded (blue) or no change (NC, grey) in Sox9 otic placode expression after injection of different doses of Irx1 mRNA. These phenotypes were not significantly different across the doses (p > 0.05). All embryos are anterior views with dorsal to the top. Numbers in brackets above bars are sample sizes. |
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Fig. 9. Increased Irx1 alters placode gene expression. (A) A low dose (200 pg) of Irx1 mRNA expanded the Sox11 PPR domain (between the red arrows) compared to control side (between the black arrows); in contrast, a higher dose (400 pg) reduced it. nt, neural tube. (B) Percentages of embryos showing reduced (orange), expanded (blue) or no change (NC, grey) in Sox11 PPR domain after injection of different doses of Irx1 mRNA. There was no difference between 400 pg and 800 pg (p > 0.05). (C) 800 pg of Irx1 mRNA expanded the Sox11 PPR domain (between the red arrows) in a minority of cases (see B), but in a majority of cases it also caused ectopic Sox11 expression in the lateral ectoderm (outlined by red dashes). (D) Percentages of embryos showing reduced (orange), expanded (blue) or no change (NC, grey) in Sox11 PPR domain after activation of Irx1-EnR-hGR at st 14 or st 16. Analyses were performed as described in Fig. 4. Each experimental group was significantly different from the no Dex group, but not significantly different from each other (p > 0.05). Control, uninjected embryos treated with Dex did not show an asymmetry in Sox11 expression (Dex st 14: 0%, n = 14; Dex st 16: 4.5%, n = 22). (E) Two examples showing that treatment of Irx1-EnR-hGR injected embryos with Chx 40 min before st 14 Dex treatment resulted in ectopic Sox11 expression throughout the lateral ectoderm (red arrows) compared to discrete PPR expression (between black arrows) and neural plate (np) expression on control side. (F) A low dose (200 pg) of Six1 mRNA expanded the Sox11 PPR domain (between red arrows) compared to control side (between the black arrows), whereas a high dose (800 pg) reduced it. (G) Percentages of embryos showing reduced (orange), expanded (blue) or no change (NC, grey) in Sox11 PPR domain after injection of different doses of Six1 mRNA. 800 pg showed a significantly different frequency compared to 200 pg (*, p < 0.05), but not 400 pg. (H) Percentages of embryos showing reduced (orange), expanded (blue) or no change (NC, grey) in Sox11 PPR domain after activation of Six1-hGR at st 14 or st 16. Analyses were performed as described in Fig. 4. Each experimental group was significantly different from the no Dex group, but not significantly different from each other (p > 0.05). Control, uninjected embryos treated with Dex did not show an asymmetry in Sox11 expression (Dex st 14: 0%, n = 14; Dex st 16: 4.5%, n = 22). (I) Irx1 expression in two placodes (black arrows) is distinct on the control side but nearly undetected on the Sox11-MO injected side (red arrows) in nearly half of embryos. (J) Increasing Sox11 prevents Irx1 expression from resolving into distinct placodes, indicated on the control side by black arrows. It remains broad and faint (between red arrows), as is typical of an earlier stage PPR. (K) Increasing Sox11 reduces Irx1 otic expression (red arrow) compared to control side (black arrow) of same embryo. e, eye; nt, neural tube. A, E, F, I, and J are anterior views; C is an anterior-lateral view; K are lateral views; all with dorsal to the top. |
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Fig. 10. Increased Irx1 reduces neural stem and neural differentiation genes in placodes. (A) Left: increased Irx1 reduced the Sox2 placode domain (red arrow) compared to control side (between black arrows) in the majority of cases. Right: expression was expanded in the lateral ectoderm along the cranial neural border in some cases. (B) Left: increased Irx1 reduced the Sox3 placode domain (red arrow) compared to control side (between black arrows) in the majority of cases. Right: expression was expanded in the lateral ectoderm along the cranial neural border in some cases. (C) Increased Irx1 reduced p27, NeuroD and Tubb2 in their placode domains (red arrows) compared to control side (black arrows). (D) Increased Irx1 also reduced these three genes in embryos in Six1 morphants. Black arrows denote control sides; red arrows denote injected sides. np, neural plate; nt, neural tube. All embryos are anterior views with dorsal to the top. |
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Fig. S1. (A) Sequences of the two antisense morpholino oligonucleotides (Six1-MO1, Six1-MO2) used to knock down Six1 translation, aligned with the sequences of the endogenous, wild type Six1 mRNA and the 5’ Myc-tagged (MT) rescue mRNA. MT-Six1-rescue mRNA contains 6 Myc-tags (proximal sequence in light blue font) 5’ to the two ATG start codons (bold in wildtype Six1). It also contains three mutated nucleotides in the Six1 ORF (red font) that do not change the amino acid code. Underlined are those nucleotides in the MT-Six1-rescue mRNA that are not complementary to either MO. (B) Validation of efficacy and specificity of Six1-MOs. Expression of the MT-Six1-rescue mRNA is high when injected alone into oocytes (-MO), and its expression is unaffected by previous injection with Six1-MO1+MO2 (+MO). Expression of an mRNA that contains the native Six1 5’UTR and a 3’Flag tag (5’UTR-Six1-3’Flag) is high when injected alone into oocytes (-MO), but translation is prevented in oocytes previously injected with Six1-MO1+MO2 (+MO). Expression of 5’Flag-Six1 and 3’Flag Six1mRNAs in injected oocytes also are shown. Uninjected lane = control oocyte lysates. (C) Uninjected Xenopus tropicalis embryo from same clutch as those shown in (D) showing normal Irx1 expression in the neural tube (nt) and otocyst (black arrow). e, eye (D) Six1 F0 mutants created by CRIPSR-Cas9 injections show normal Irx1 expression in the neural tube (nt), but loss of expression in the otic vesicle (red arrows). These Xenopus tropicalis embryos were created by microinjecting Cas9 protein plus sgRNAs, designed by the National Xenopus Resource and demonstrated by them to efficiently cause N-terminal Six1 mutations, into the fertilized egg during the 2017 Xenopus Genome Editing Workshop. |
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