The zic1 gene is an activator of Wnt signaling

Abstract

The zic1 gene plays an important role in early patterning of the Xenopus neurectoderm. While Zic1 does not act as a neural inducer, it synergizes with the neural inducing factor Noggin to activate expression of posterior neural genes, including the midbrain/hindbrain boundary marker engrailed-2. Since the Drosophila homologue of zic1, odd-paired (opa), regulates expression of the wingless and engrailed genes and since Wnt proteins posteriorize neural tissue in Xenopus, we asked whether Xenopus Zic1 acted through the Wnt pathway. Using Wnt signaling inhibitors, we demonstrate that an active Wnt pathway is required for activation of en-2 expression by zic1. Consistent with this result, Zic1 induces expression of several wnt genes, including wnt1, wnt4 and wnt8b. wnt1 gene expression activates expression of engrailed in various organisms, including Xenopus, as demonstrated here. Together, our data suggest that zic1 is an upstream regulator of several wnt genes and that the regulatory relationships between opa, wingless and engrailed seen in Drosophila are also present in vertebrates.

Emerging roles for zic genes in early development

“…Another study determined that the C-terminus of Zic2 contains both activation and repression domains (Brown et al, 2005). Furthermore, Zic proteins devoid of the regions N-terminal to the zinc finger domain tend to act as dominant interfering proteins in Xenopus embryos (Kitaguchi et al, 2000;Nakata et al, 2000;Houston and Wylie, 2005;Fujimi et al, 2006;Merzdorf and Sive, 2006), suggesting that the N-termini may mediate positive regulatory activities. The N-and C-terminal domains of Zic proteins represent potential cofactor binding sites that are likely to modulate Zic activities, either to enhance or inhibit transcriptional activation or repression.…”

“…One such gene that is induced by all Xenopus zic genes is the midbrain/hindbrain boundary marker en-2 (Nakata et al, 1997(Nakata et al, , 1998Kuo et al, 1998;Fujimi et al, 2006). Additional genes induced by expression of zic1 include the dorsal neural tube marker pax3 (midbrain, hindbrain, spinal cord; Bang et al, 1997) and various dorsally expressed wnt genes, including wnt1 (midbrain/hindbrain boundary, hindbrain; Wolda et al, 1993), wnt4 (forebrain/midbrain boundary, midbrain; McGrew et al, 1992), and wnt8b (forebrain/midbrain boundary, midbrain; Cui et al, 1995) (Kuo et al, 1998;Merzdorf and Sive, 2006). zic1 also activates the hindbrain genes krox20, hoxD1, and Xfeb (Kuo et al, 1998;Li et al, 2006).…”

“…Zic1 is required for expression of the MHB genes en-2 and wnt1 in Xenopus. Since an active Wnt pathway is required for activation of en-2 expression by Zic1, Zic1 most likely induces wnt1 expression, which in turn induces the en-2 gene (Merzdorf and Sive, 2006). Thus, Zic1 may be an important factor in regulating the expression of a subset of genes involved in formation of the MHB.…”

“…zic gene expression precedes wnt11 expression in this region (Marcelle et al, 1997;Sun Rhodes and Merzdorf, 2006). Although Zics regulate the expression of wnt genes in neural tube development (Merzdorf and Sive, 2006), it is not clear whether this is true during somite development. It will be of significant interest to determine how zic genes participate in the regulatory pathways that guide somite development and how the role of zic genes might differ during neural tube and somite development.…”

Unique microRNA profile in Dupuytren's contracture supports deregulation of β-catenin pathway

“…ZIC1, the target of miR-101, has been suggested to be an upstream regulator of several Wnt pathway genes including WNT1, WNT4, and WNT8B, 32 and its expression has been described in fibroproliferative diseases including Dupuytren's contracture. 33 Furthermore, Degreef et al 34 reported on coexpression of ZIC1 and b-catenin in Dupuytren's contracture samples.…”