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Identification of Downstream Genes of the Ascidian Muscle Determinant Gene Ci-Macho1

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Identification of Downstream Genes of the Ascidian Muscle Determinant Gene Ci-Macho1 View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Developmental Biology 274 (2004) 478–489 www.elsevier.com/locate/ydbio Genomes & Developmental Control Identification of downstream genes of the ascidian muscle determinant gene Ci-macho1 Kasumi Yagi*, Nori Satoh, Yutaka Satou Department of Zoology, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan Received for publication 22 May 2004, revised 9 July 2004, accepted 14 July 2004 Available online 25 August 2004 Abstract Autonomous differentiation of primary muscle cells in ascidian embryos is triggered by a maternal determinant recently identified as the macho-1 gene. macho-1 encodes a transcription factor of the Zic family with five C2H2 zinc-finger motifs. In the present study, we firstly performed a screen, using a quantitative PCR method, of genes encoding transcription factors and components in major signaling pathways to identify those regulated downstream of Ci-macho1 in early embryos of Ciona intestinalis. The amount of transcripts for a total of 64 genes was altered at the 32-cell stage depending on the Ci-macho1 activity level. Whole-mount in situ hybridization assays revealed that the alteration of expression for at least 13 of them was adequately visualized to confirm the results of quantitative PCR. Second, we determined a possible binding sequence of Ciona macho1. macho1 recombinant proteins of both C. intestinalis and Ciona savignyi recognized a sequence, 5V-GCCCCCCGCTG-3V, that resembles the mammalian Zic binding site. In addition, most of the genes identified as potential Ci-macho1 downstream genes, in particular Ci-Tbx6b and Ci-snail, possessed plausible Ci-macho1-binding sequences in their 5V upstream region, suggesting their direct activation by Ci-macho1. Furthermore, some of the genes including three Wnt genes noted in the quantitative analyses implied that Ci-macho1 is involved in the differentiation of endoderm and mesenchyme via intracellular communications. D 2004 Elsevier Inc. All rights reserved. Keywords: Ciona intestinalis; Autonomous muscle differentiation; Determinant; macho1; Binding sequence; Downstream genes\ Introduction species), which lie on both sides of the notochord in the tail, and 28 cells in the anterior and middle parts originate from the Maternal information stored in the egg cytoplasm plays a B4.1 blastomeres of a bilaterally symmetrical 8-cell embryo. pivotal role in the establishment of embryonic axes or Differentiation of these B-line or primary muscle cells occurs specification of embryonic cells. Ascidians have provided a autonomously depending on a maternally provided muscle classical as well as a modern experimental system for determinant(s). Experimental approaches toward character- identifying morphogenetic determinants and for elucidating izing the molecular nature of the determinant suggested that it their function in subsequent differentiation (for recent is provided as maternal mRNA, localized to the so-called reviews, see Corbo et al., 2001; Jeffery, 2001; Nishida, myoplasm after fertilization, and segregated into blastomeres 2002a,b; Satoh, 2001, 2003). Muscle formation in ascidians of the B-line muscle lineage, and that the protein product is the best-studied system of autonomous differentiation. A from the mRNA triggers the genetic cascade responsible for tadpole-type larva of Ciona intestinalis has 36 unicellular and muscle differentiation (Deno et al., 1984; Marikawa et al., striated muscle cells (the number varies a little depending on 1994; Nishida, 1990; Whittaker, 1973, 1980). By a subtractive hybridization screen using Halocynthia roretzi embryos, Nishida and Sawada (2001) isolated * Corresponding author. Department of Zoology, Graduate School of Science, Kyoto University, Kitashirakawa Oiwake-cho, Sakyo-ku, Kyoto macho-1, which encodes a Zic-like zinc-finger protein with 606-8502, Japan. Fax: +81 75 705 1113. transcription factor activity. They showed that maternally E-mail address: [email protected] (K. Yagi). provided macho-1 mRNA is segregated to the myoplasm, 0012-1606/$ - see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ydbio.2004.07.013 K. Yagi et al. / Developmental Biology 274 (2004) 478–489 479 that overexpression and ectopic expression of the gene several genes including Ci-Tbx6b and Ci-snail are regulated promote ectopic differentiation of muscle cells, and that by Ci-macho1 and they possess plausible Ci-macho1- downregulation of the gene function results in failure of the binding sequences in their 5V upstream region, suggesting differentiation of B-line muscle cells. In a previous study, that they are direct target genes of Ci-macho1. we isolated orthologous genes of macho-1 from C. intestinalis (Ci-macho1) and Ciona savignyi (Cs-macho1), and showed that they are also responsible for initiation of Materials and methods muscle differentiation (Satou et al., 2002a). The molecular function of the macho1 protein and the Ascidian eggs and embryos genetic cascade triggered by macho1 remain to be clarified. So far, some transcription factor genes, including Tbx6 C. intestinalis individuals were maintained under con- (Mitani et al., 1999), snail (Fujiwara et al., 1998), and ZicL, stant light to induce oocyte maturation. Eggs and sperm which is another Zic family gene (Imai et al., 2002), have were obtained surgically from the gonoduct. After insemi- been shown to be involved in the differentiation of ascidian nation, eggs were reared at about 188C in Millipore-filtered muscle cells. The expression of Ci-Tbx6 genes starts at the seawater (MFSW) containing 50 Ag/ml streptomycin 16-cell stage (Takatori et al., 2004), Ci-snail expression is sulfate. detected from the 32-cell stage onwards (Fujiwara et al., 1998; Erives et al., 1998), and the expression of ZicL is Injection of morpholino antisense oligonucleotides and detected from the 32-cell stage (Imai et al., 2002; Yagi et al., synthetic capped mRNA 2004). In Ciona embryos, the expression of muscle protein genes becomes evident after gastrulation (for example, Cs- A 25-mer morpholino antisense oligonucleotide for Ci- MA1, Chiba et al., 1998). The actual function of these macho1 (hereafter simply called Ci-macho1 MO), 5V- transcription factor genes in the activation of muscle protein ATCCCATCGTACCAGTAAAGGCCAT-3V, was order- genes and their relationships with macho1 remain to be made (Gene Tools, LLC). The target sequence contained clarified. the first methionine codon (underlined). MOs act efficiently Recent decoding of the C. intestinalis draft genome to knock down Ciona developmental genes (Satou et al., allowed us to investigate this issue on a genome-wide scale. 2001a). Control embryos injected with a universal control The Ciona genome sequence (about 160 Mb) contains fewer MO (5V-CCTCTTACCTCAGTTACAATTTATA-3V,Gene paralogues than are usually seen in vertebrates, and many Tools, LLC) did not cause any irrelevant gene expression. genes represent their original features before the duplication In vitro synthesized capped mRNA of Ci-macho1 was that is presumed to have occurred twice in vertebrate prepared from cDNA cloned into pBluescript RN3 vector evolution (Dehal et al., 2002; Satoh et al., 2003; Satou and using a Megascript T3 kit (Ambion). Microinjections were Satoh, 2003). Taking advantage of these traits, as a scaffold performed as previously described (Imai et al., 2000), and for a future thorough understanding of development, we each injection contained about 30 pl of solution with 0.5 compiled a comprehensive list of C. intestinalis genes, mM MO or 1.2 mM synthesized mRNA. encoding transcription factors and components of major signaling transduction pathways (hereafter, signaling genes), Quantitative RT-PCR (real-time PCR) and determined their spatiotemporal expression profiles by whole-mount in situ hybridization and quantitative PCR Total RNA extraction from embryos and cDNA synthesis (Imai et al., 2004). The list includes, for transcription factor with oligo(dT) primers were performed as described genes, those encoding a factor with bHLH, homeobox, Fox, previously (Satou et al., 2001b). Each quantitative PCR ETS, bZIP, HMG, or T-box domains and specific categories was carried out using 0.4 embryo equivalent quantity of of zinc-fingers (Satou et al., 2003a; Wada et al., 2003; Yagi et cDNA as template in 10 Al of reaction mixture consisting of al., 2003; Yamada et al., 2003), and for signaling genes those 1Â SYBR Green Master Mix and 300 nM of each primer. encoding a major component involved in signaling pathways The relative amounts of mRNA for each of comprehen- of receptor tyrosine kinases, MAPK, Notch, TGFh, Wnt, and sively annotated genes encoding transcription factors and JAK/STAT (Hino et al., 2003; Satou et al., 2002b, 2003b). major components involved in signaling pathways (Imai et In the present study, we conducted a genome-wide screen al., 2004) were examined (see Supplementary Table 1). for these transcription factor genes and signaling genes Reactions were performed using the ABI Prism 7000 regulated by Ci-macho1 in vivo. Quantitative analysis and Sequence Detection System (Applied Biosystem) according whole-mount in situ hybridization analysis identified genes to manufacturer’s specifications with universal amplifica- whose zygotic expression is under the control of Ci-macho1 tion conditions. Dissociation curves were used to confirm from the early cleavage stage. In addition, we determined
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