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J Biol Chem
2010 Oct 01;28540:30814-24. doi: 10.1074/jbc.M110.142869.
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ZFP423 coordinates Notch and bone morphogenetic protein signaling, selectively up-regulating Hes5 gene expression.
Masserdotti G
,
Badaloni A
,
Green YS
,
Croci L
,
Barili V
,
Bergamini G
,
Vetter ML
,
Consalez GG
.
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Zinc finger protein 423 encodes a 30 Zn-finger transcription factor involved in cerebellar and olfactory development. ZFP423 is a known interactor of SMAD1-SMAD4 and of Collier/Olf-1/EBF proteins, and acts as a modifier of retinoic acid-induced differentiation. In the present article, we show that ZFP423 interacts with the Notch1 intracellular domain in mammalian cell lines and in Xenopus neurula embryos, to activate the expression of the Notch1 target Hes5/ESR1. This effect is antagonized by EBF transcription factors, both in cultured cells and in Xenopus embryos, and amplified in vitro by BMP4, suggesting that ZFP423 acts to integrate BMP and Notch signaling, selectively promoting their convergence onto the Hes5 gene promoter.
FIGURE 3. Selective, cooperative activation of ESR1 gene expression by Nact and ZFP423 in Xenopus embryos. A and B, whole mount in situ hybridization analysis of Xenopus Zfp423 gene expression in stage 17 (frontal view) and stage 22 (lateral view, head to the left) embryos, respectively: the gene is widely expressed starting in the neural plate/tube first (arrow), and then moving to the cranial neural crest (arrowhead). C, whole mount in situ hybridization analysis of ESR1 gene expression in embryos injected unilaterally (bracket) with Zfp423 (600 pg) and/or Nact (100 pg), as indicated. LacZ (blue stain) serves as an indicator of the injected side. Note strong ESR1 expression after coinjection of Nact and Zfp423. F, embryo injected unilaterally (bracket) with 1 ng of Zfp423. G, embryo injected unilaterally (bracket) with 1 ng of Zfp423 and 400 pg of DeltaStu, encoding a dominant negative Notch ligand. Note disappearance of ESR1 signal on the co-injected side. H and I, unilateral injection (bracket) of a Zfp423 morpholino oligonucleotide (H) and of a control morpholino (I) (see xperimental Procedures. Note disappearance of ESR1 signal on the injected side in embryos injected with Zfp423-specific morpholino unlike those injected with the control morpholino. J, Zfp423 overexpression selectively up-regulates ESR1 but not Hairy1 or Nrarp in Xenopus embryos. Whole mount in situ hybridization analysis of ESR1, Hairy1, and Nrarp gene expression in embryos injected unilaterally with Zfp423 (300 pg, arrow) in a dorsal blastomere. Note expanded ESR1 expression domain (J), but reduced/unaffected expression of Hairy1 (K) and Nrarp (L) on the injected side. Gfp was coinjected with Zfp423 as a lineage tracer (not shown).
FIGURE 6. EBF TFs reduce ZFP423-NICD-mediated Hes5 gene expression in vitro and in vivo. A, RT-qPCR analysis of Hes5 gene expression in P19 cells transfected with the indicated constructs. Note that Ebf1, Ebf2, or Ebf3 alone does not affect basal Hes5 expression. B, whole mount in situ hybridization analysis of ESR1 gene expression in embryos injected unilaterally (bracket) with Nact (100 pg) and Zfp423 (600 pg) and/or XEbf2 (100 pg) or XEbf3 (100 pg). E and F, whole mount in situ hybridization analysis of ESR1 gene expression in embryos injected unilaterally with XEbf2 (100 pg) or XEbf3 (100 pg), as indicated. Note slightly increased ESR1-positive cells in XEbf2- and XEbf3-injected embryos (arrow). B, LacZ (blue stain) serves as an indicator of the injected side.
Supplemental Figure 2. Zfp423 expression during Xenopus laevis development. Whole mount in situ hybridization analysis of Zfp423
gene expression in embryos at different stages of development (stage 17 and 22, dorsal view; stage 28 and 34 lateral view).
znf423 (zinc finger protein 423 ) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 17, dorsal view, anterior up.
znf423 (zinc finger protein 423 ) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 22, dorsal view, anterior up.
znf423 (zinc finger protein 423 ) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 28, lateral view, anteriorleft, dorsal up.
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