Quigley IK, Stubbs JL, Kintner C.

GM07650 NIGMS NIH HHS , R01 GM076507-07 NIGMS NIH HHS , F32 DK084706-01A2 NIDDK NIH HHS , R01 GM076507 NIGMS NIH HHS , F32 DK084706 NIDDK NIH HHS

                infertility

Xla Wt + foxi1-GR + DEX(Fig 3.B, E)

	Fig. 1. Expression of ion transport genes in the X. laevis larval skin. Whole-mount in situ hybridization on stage 26 tadpoles was used to localize transcripts encoding proteins involved in ion transport, including (A,D) two subunits of the H+v-ATPase, (B,E) two isoforms of carbonic anhydrase and (C) a pendrin-like anion exchanger. Note that these genes are expressed in scattered cells that are absent from the posterior and anterior areas of skin, in contrast to the pattern of ciliated cells marked by α-tubulin expression (F). A magnified view is shown in the neighboring panels.
	Fig. 2. foxi1-HGR strongly upregulates the expression of ionocyte genes. (A-O) Xenopus embryos were injected at the 2-cell stage with mRNAs encoding foxi1-HGR or foxa1-HGR, activated Notch (ICD) or with both foxi-HGR and ICD, treated with dexamethasone (DEX) at stage 12, fixed at stage 26 and stained for expression of the indicated genes by whole-mount in situ hybridization. foxi1-HGR, but not foxa1-HGR, strongly induced the ectopic expression of ca12 (A) and atp6V0A4 (B), even in the presence of ICD (J,K) but had no effect, or a slight inhibitory effect, on the expression of the ciliated cell marker α-tubulin (C). n-lacZ RNA injections (nβgal) served as a negative control (M-O).
	Fig. 3. foxi1-HGR promotes INC formation. (A-D) Two-cell Xenopus embryos were injected with RNA encoding foxi1-HGR and ICD along with mRFP RNA as a tracer, treated with DEX at stage 12, fixed at stage 26, and stained with anti-acetylated tubulin (green) to identify ciliated cells (CCs). Shown is a confocal image of the skin in embryos injected with just RFP (A), foxi1-HGR (B), ICD (C) or with both foxi1-HGR and ICD RNA (D). (E) Quantification of different cell types in the skin under the indicated experimental conditions. CCs stained with the acetylated tubulin antibody (green) were classified as defective if they failed to form cilia. INCs and outer cells (OCs) were scored based on their characteristic small and large apical domain, respectively. Error bars indicate + s.d. All values are significantly different relative to the control, based on a two-tailed t-test (P≤0.005). Scale bar: 20 μm.
	Fig. 4. INC subtypes. (A) Analysis of Xenopus larval skin at stage 26 using two-label FISH probes for ae1 (red) and pendrin (green) identifies two approximately equal populations of INCs. (B-E′) Embryo injected at the 2-cell stage with mGFP RNA was fixed and stained at stage 26 with B1 (red) and ae1 (blue) antibodies. Note that INCs with strong apical B1 staining (B, arrow) also stain with ae1 (C, arrow) whereas those with basolateral B1 staining (B, arrowhead) do not. z-section through cells with apical B1 staining (compare arrowheads in D and E) shows that ae1 localizes basolaterally (D,D′), whereas in cells with cytosolic or basolateral B1 staining ae1 is absent (E,E′). (F-H) pendrin-GFPtr embryos were fixed at stage 26 and stained with antibodies to B1 (red) and E-cadherin (blue). Shown is B1 staining (F), GFP expression (G), or a merge of all three channels (H). (I) pendrin-GFPtr embryos were injected with mRFP RNA (red) to label cell boundaries and stained with ae1 antibody (blue). CC, ciliated cell. Asterisk marks a small population of INCs that do not stain with or express ae1, pendrin or B1. Scale bar: 20 μm.
	Fig. 5. Notch signaling directs INC subtype specification. (A,B) Wild-type distribution of alpha- and beta-INCs. (C,D) High doses of HMMmut mRNA increase both INC subtypes, but favor beta-INC differentiation, as determined by ae1 and pendrin-GFP staining or by atp6v1b1 localization (not shown). (E) Notch signaling was titrated either with two decreasing doses of HMMmut to block signaling or three increasing doses of ICD to promote signaling, and then embryos were assayed for proportions of alpha- and beta-subtypes by confocal microscopy and cell counting. Cells were counted from at least three confocal fields from several embryos, typically eight. Raw INC subtype numbers were then converted into percentages and arcsine transformed. Two-tailed t-tests indicated significant differences between each dose (P≤0.05) except for the two HMMmut doses, which were not significantly different (the two leftmost columns). Error bars indicate + s.d. Scale bar: 40 μm.
	Fig. 6. ubp1 regulates beta-INC specification. (A,B) Two-color FISH indicates that ubp1 is co-expressed with pendrin, which marks beta-INCs (A), but not with ae1, a marker of alpha-INCs (B). The arrow marks an ae1-expressing cell and the arrowhead marks a ubp1-expressing cell. (C-E) Xenopus embryos were injected with ubp1-HGR RNA at the 2-cell stage, treated with DEX at stage 12 and then fixed at stage 26 to quantify the number of alpha-INCs and beta-INCs using three different approaches: two-label FISH for ae1 (red) and pendrin (green) mRNA (C); pendrin-GFPtr transgenics (green) with ae1 antibody staining (blue) and mRFP (red) (D); or mGFP (green) and B1 antibody staining (red) (E). Arrows mark alpha-INCs. Cells were counted from at least three random fields (196 μm2 of embryo surface) from at least five embryos, typically eight; fields shown are 98 μm2. Error bars indicate ± s.d. All values between a given INC subtype under various conditions are significantly different relative to the control, based on a two-tailed t-test (P≤0.005). Scale bar: 20 μm.
	Fig. 7. ubp1-HGR converts foxi1-HGR-induced alpha-INCs into beta-INCs. (A-F) Xenopus embryos were injected at the 2-cell stage with foxi1-HGR or with both foxi1-HGR and ubp1-HGR RNA, along with mGFP RNA as a tracer. Injected embryos were treated with DEX at stage 12, fixed at stage 26, and then stained with B1 (red, upper panels) and with ae1 (blue, lower panels) antibodies. (G) pendrin-GFPtr embryos were injected with foxi1-HGR, ubp1-HGR and mGFP as tracer, and then stained with ae1 antibody (blue). (H) Based on ae1 and B1 staining, alpha-INCs and beta-INCs per field were scored under the various conditions; each field represents 196 μm2 of embryo surface. Error bars indicate ± s.d. Scale bar: 20 μm.
	atp6v0a4 (ATPase, H+ transporting, lysosomal V0 subunit a4 ) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, lateral view, anterior left, dorsal up. (magnified view to right).
	ca2 (carbonic anhydrase 2) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, lateral view, anterior left, dorsal up (magnified view to right).
	slc26a4l (solute carrier family 26 member 4 like) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, lateral view, anterior left, dorsal up (magnified view to right).
	atp6v1b1 (ATPase, H+ transporting, lysosomal 56/58kDa, V1 subunit B1) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage26, lateral view, anterior left, dorsal up (magnified view to right).
	ca12 (carbonic anhydrase XII) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26 lateral view, anterior left, dorsal up (magnified view to right).
	Fig. S1. Phylogenetic relationships of PSC genes. To confirm orthology of X. laevis PSC genes, we performed phylogenetic analysis with 1000 bootstrapping iterations of the neighbor-joining method on protein sequences in ClustalX (Quigley et al., 2010). Genes characterized further in this paper are marked in red and underlined. (A) X. laevis ae1 is an ortholog of human and mouse AE1. Accession numbers: human AE1 (4507021), mouse Ae1 (6755560), zebrafish ae1 (38198629), Xenopus slc4a7 (148225418) and Xenopus ae1 (147900281). A close examination of the curated X. laevis locus suggests a sequencing error that inserted a premature stop codon; we base this inference on strong conservation of downstream sequence. Moreover, our ae1 antibody is directed towards a peptide sequence downstream of this curated stop, suggesting that the sequence to which it binds is translated (Wainwright et al., 1989). Correspondingly, we edited the X. laevis sequence to include this conserved downstream region. (B) X. laevis pendrin and pendrin-like loci are the result of a recent gene duplication. Accession numbers: human Pendrin (4505697), mouse Pendrin (6755022), zebrafish pendrin (125814600), Xenopus pendrin (148236113) and Xenopus pendrin-like (147903861). Our bioinformatic analysis hints that there might be one or more additional uncharacterized X. laevis pendrin orthologs (not shown). (C) X. laevis foxi1 is an ortholog of human and mouse Foxi1. Given the role of X. laevis foxi1 in early ectodermal patterning (Mir et al., 2007) and different roles for foxi1 orthologs in both epidermal and PSC specification in zebrafish (Hsiao et al., 2007; Janicke et al., 2007) we sought to clarify these evolutionary relationships. Zebrafish foxi3a and foxi3b paralogs group with Xenopus, mouse and human Foxi1, suggesting a common role for these genes in PSC differentiation. Accession numbers: human Foxi1 (21618327), mouse Foxi1 (226693365), zebrafish foxi1 (32189364), zebrafish foxi2 (68226724), zebrafish foxi3a (129270185), zebrafish foxi3b (38708001), Xenopus foxi1 (148221999) and Xenopus foxj1 (148233368). (D) X. laevis ubp1 is a derived transcription factor of the grainyhead family. While X. laevis ubp1 most closely resembles lbp1a of other species in sequence similarity, a close syntenic analysis suggests that direct orthologs of ubp1 were not maintained in the human and mouse lineages (not shown). Given that grainyhead proteins heterodimerize for nuclear localization and transcription factor activity (Yoon et al., 1994; Sato et al., 2005; Katsura et al., 2009), we speculate that other grainyhead proteins are performing a function similar to that of Xenopus ubp1 in the kidneys of these mammals. Accession numbers: human LBP1A (189491630), mouse Lbp1a (134032032), zebrafish lbp1a (167621514), human CP2 (21361278), Xenopus cp2 (147903721), human LBP9 (7657299), mouse Tcfcp2l1 (109733355), Xenopus cp2l1 (148237830), Xenopus ubp1 (148886714), Xenopus grainyhead-like 1 (148230919), Xenopus grainyhead-like 2 (58332528) and Xenopus grainyhead-like 3 (147903002). References Quigley, I. K., Schmerer, M. W. and Shankland, M. (2010). A member of the six gene family promotes the specification of P cell fates in the O/P equivalence group of the leech Helobdella. Dev. Biol. 344, 319-330. Wainwright, S. D., Tanner, M. J., Martin, G. E., Yendle, J. E. and Holmes, C. (1989). Monoclonal antibodies to the membrane domain of the human erythrocyte anion transport protein. Localization of the C-terminus of the protein to the cytoplasmic side of the red cell membrane and distribution of the protein in some human tissues. Biochem. J. 258, 211-220.
	Fig. S2. Expression of PSC genes increases in embryos with disabled Notch signaling. (A-F) Whole-mount in situ hybridization of stage 26 tadpoles that were injected on one side at the 2-cell stage with RNA encoding HMMmut to block Notch signaling in the developing skin, along with RNA encoding β-galactosidase as a tracer. The injected side was identified by X-gal staining (light blue) and RNA expression was revealed by NBT/BCIP staining (light purple). Shown is the uninjected (left panel) and injected side (right panel) for transcripts encoding foxi1 (A), two subunits of the H+v-ATPase involved in proton transport (B,D), an isoform of carbonic anhydrase (C), pendrin-like (E) and the ciliated marker α-tubulin as a control (F).
	Fig. S3. Temporal expression of PSC genes. (A-DD) Shown is the expression of foxi1 (A-E), atp6v0a4 (F-J), pendrin (K-O), pendrin-like (P-T), ae1 (U-Y) and ubp1 (Z-DD) across different stages of embryonic development. Embryonic stage (Nieuwkoop and Faber, 1967) is marked in the lower left corner. Note that expression of foxi1 precedes any other PSC marker (compare A with F,K,P,U,Z), that expression of atp6v0a4, pendrin, pendrin-like and ubp1 are all roughly simultaneous (F,K,P,Z), and that ae1 expression does not initiate until several stages later (U). Number of cells expressing pendrin, pendrin-like or ae1 is a subset of all PSCs (for example, compare I with N,T,X; see also Figs 4 and 5 in the main text). Finally, note the ae1 expression in ventral blood islands (arrowhead in Y); a splice variant of mammalian ae1 is strongly expressed in red blood cells (Kopito and Lodish, 1985). References Kopito, R. R. and Lodish, H. F. (1985). Primary structure and transmembrane orientation of the murine anion exchange protein. Nature 316, 234-238. Nieuwkoop, P. D. and Faber, J. (1967). Normal Table of Xenopus Laevis, Amsterdam: North Holland.
	Fig. S4. foxi1-HGR promotes cell intercalation. Donor embryos were injected with RNA encoding membrane-targeted RFP as a tracer, while hosts were injected with RNA encoding foxi-HGR, ICD, both together, along with membrane-targeted mGFP RNA as a tracer. At stage 10, a small patch of outer layer was removed from donor embryos and transplanted homotopically onto the inner layer of a host embryo. At stage 12, the embryos were treated with DEX and, at stage 24, fixed, stained with Z0-1 antibodies (red) and imaged on the confocal microscope. (A-F) Shown is the ZO-1 staining (A,D), GFP expression in intercalating cells (B,E) and merged image (C,F) in host embryos injected with ICD RNA (A-C) or both foxi1-HGR and ICD RNA (D-F). Note that ICD completely eliminates intercalating GFP-labeled cells, whereas foxi1-HGR induces them. Scale bar: 20 µm. (G) Quantification of intercalating cells (ICs) and outer cells (OCs) under the indicated experimental conditions. Data were collected from four fields from four embryos. Error bars indicate + s.d.
	Fig. S5. GFP expression in pendrin-GFPtr larvae and atp6v1b1 staining in control and b1 morphants. Pendrin-GFPtr larvae were injected at the 2-cell stage with (A-C) a control morpholino or (D-F) with a morpholino directed against X. laevis atp6v1b1 and stained with antibodies against GFP and atp6v1b1. Note the loss of atp6v1b1 staining in the PSCs of b1 morphants (E,F). Scale bars: 80 µm.
	Fig. S6. Protein alignment of ubp1 from selected vertebrate species. Full-length X. laevis ubp1 was aligned to the closest ortholog in mouse, rat, human and zebrafish. Percentage identity from X. laevis to mouse is 50%, to rat is 51%, to human is 52%, and to zebrafish is 48%. Accession numbers: Xenopus ubp1 (148886714), human LBP1A (189491630), mouse Lbp1a (134032032), zebrafish lbp1a (167621514) and rat Lbp1a (109485524).
	Fig. S7. ubp1 is controlled by Notch and expressed in beta-INCs. (A-D) ubp1-expressing cells increase in embryos where Notch is blocked using a dominant-negative mastermind (HMMmut) (compare A with B), and decrease in embryos where Notch is constitutively active using ICD (compare C with D). (E-H) Embryos were injected on one side at the 2-cell stage with RNA encoding ubp1-HGR, treated with DEX at stage 12, and then processed at stage 26 for the expression of pendrin and ae1 by whole-mount in situ hybridization. Note that ubp1-HGR induces more pendrin-expressing cells (compare E with F) but decreases the number of ae1-expressing cells (compare G with H).
	Fig. S8. Timing of INC response to ubp1 misexpression. Embryos were injected with ubp1-HGR mRNA and treated with DEX at stage 12, 18 or not at all, and alpha- and beta-INC numbers were assayed by B1 and ae1 antibody staining. Embryos without DEX treatment produced similar numbers to uninjected wild types. In embryos treated with DEX at stage 18 (after the initiation of wild-type ae1 expression, see Fig. S3U,V), ubp1-HGR induces the formation of more beta-INCs, but does not repress alpha-INC formation. Error bars indicate ± s.d.
	Fig. 9. foxi1-HGR induces ae1 and alpha-INCs. (A-D) Embryos were injected at the 2-cell stage with foxi1-HGR, treated with DEX at stage 12 and then processed for ae1 and pendrin expression by whole-mount in situ hybridization. Shown are representative examples of uninjected and injected regions. Note that foxi1-HGR induces a massive increase in ae1 expression, but only a small increase in the number of cells expressing pendrin. (E,F) Example of a control transplant (E) stained with antibody to ae1 (F). (H,I) Example of a transplant onto a host injected with foxi1-HGR RNA (H) and stained with ae1 antibodies. The arrowhead marks ae1-negative INC (I). (G) Transplant assay where the outer layer is removed from ectoderm at stage 10 from a mGFP-injected host and placed on the inner layer of a host injected with mRFP or with both foxi1-HGR and mRFP RNA. INCP, intercalating non-ciliated cell precursor; CCP, ciliated cell precursor. (J) Quantification of ae1-positive and -negative INCs in control or foxi1-HGR injected hosts (three random fields from at least eight embryos per condition). Error bars indicate ± s.d. All values between a given INC subtype under the various conditions are significantly different relative to the control, based on a two-tailed t-test (P≤0.005). Scale bar: 20 µm.

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