Kota Abe Department of Biological Sciences, Graduate School of Science, University of Tokyo, Tokyo, Japan. Hiroyuki Takeda Department of Biological Sciences, Graduate School of Science, University of Tokyo, Tokyo, Japan.
Zic Family in Animal Evolution and Development
Comparative Genomics of the Zic Family Genes
- Distribution of the Zic Genes in the Animal Phylogenetic Tree
- Cardinal Amino Acid (aa) Sequence Features of Zic Family Proteins
- Zinc Finger Domain (ZFD)
- ZOC Domain
- ZFNC Domain
- Other Conserved Sequences
- Exon-Intron Organization of Zic Family Genes
- Conservation in the Nonprotein-Coding Region
- Hypotheses for the Evolutionary Processes of Zic Family Genes
- Origin of Zic Genes
- Acquisition of the Unique Features in the First and Second Zinc Finger Motif
- Evolution of the Nuclear Localization Signal (NLS)
- Animal Taxa-Selective Sequence Degeneration
- Zic Evolutionary Processes
- Evolutionary Conserved Roles in Zic Proteins
- Generation of Neural Cells
- Generation of Mesoderm
- Generation of Neural Crest Cells or CNS Lateral Border Cells
- Establishment of Metamerism
- Dorsoventral Patterning of Somites
- Establishment of Binocular Vision
Evolutionary processes in the vertebrate lineage have been proposed as follows (Figure 1.7b) (Aruga et al. 2006). Clitellate Zic is expressed in the first daughter cells of mesodermal teloblasts (Takahashi et al. 2008b).
Keller MJ, Chitnis AB (2007) Insights into the evolutionary history of the vertebrate zic3 locus from a teleost-specific zic6 gene in the zebrafish, Danio rerio. Layden MJ, Meyer NP, Pang K, Seaver EC, Martindale MQ (2010) Expression and phylogenetic analysis of the zic gene family in the development and evolution of metazoans.
Cnidarian Zic Genes
Generalized Bilaterian Zic Expression and Function
In annelids zik homologs are widely expressed in the mesoderm and in a segmentally repeated pattern in the mesoderm surrounding the chaetal sacs (Layden et al. 2010; Takahashi et al. 2008). Vertebrate and ascidian zyg homologues are also important for the specification of mesodermally derived parts of the notochord (Wada and Saiga 2002).
Cnidarian and Bilaterian Zic Homologs Derived from Single Ancestral Gene
A counterintuitive interpretation is that the elaborate domain structure of zic homologues arose once in the common ancestor of bulbils and bilaterians (Layden et al. 2010). In the sea anemone Nematostella vectensis genome, five cic homologues are present, and in the coral A genome, six cic-like genes are present.
The Cnidarian Body Plan
The tandem arrangement of four of the five zic genes in the Nematostella genome and the fact that two of the six coral genes are pseudogenes suggest that there was probably an independent expansion of zics in the anthozoans (Shinzato et al. These observations combined with the fact that only a single zic homolog is found in the draft Trichoplax genome supports that a single ancestral zic gene possessing ZOC and ZF-NC domains existed in the cnidarian-bilaterian common ancestor.
Hyzic Expression in Cnidocyte Development in Adult Hydra vulgaris Polyps
It remains unclear whether Hyzic expression in i cells regulates the development of other neuronal cells in Hydra. Hyzic co-expresses with BrdU in short and long pulses, but Cnash and Nowa require extended pulses of BrdU to be labeled (c) (This figure is adapted from figures in Lindgens et al.
Cnidarian Development
Musculature begins to form, endodermal neurogenesis begins, and the nervous system continues to mature (Layden et al. 2016b). Species-dependent cues, believed to be mediated by the apical organ, then result in settlement and metamorphosis into the juvenile polyp.
Nvzic Expression During Development of Nematostella vectensis
NvzicD is expressed in the presumptive tentacle electoderm (G and H) and individual ectodermal cells (G, arrowhead) of the planula. NvzicE is expressed in the oral ectoderm (L, arrow), presumptive tentacle (L and M) and apical tuft (M, arrow), the planula and tentacle buds (N), tentacle endoderm (O) and occasionally individual ectodermal cells in the tentacles (R, arrowhead).
Comparing Hyzic and NvzicA-E Expression Suggests an Ancestral Role for Zic Homologs Was Conserved
NvzicD expression is detected in individual cells in the tentacular endoderm, within cell lines in the mesentery, and sporadically in cells of the body column ectoderm. Ctenophores possess neurons and sponges have sensory-like cells with neuronal properties (Ludeman et al. 2014) arguing that a primitive nerve-like cell may have been present in the parahoxosis.
Concluding Remarks
Layden MJ et al (2010) Expression and phylogenetic analysis of the zic gene family in metazoan evolution and development. Saina M et al (2009) BMPs and chordin regulate patterning of the directional axis in a sea anemone.
Introduction
Based on extensive neural expression, Opa is predicted to be involved in many aspects of neural development and behavior, like other proteins of the Zic family. Pair-rule genes are part of a hierarchy of zygotic genes that create the basic metameric body plan of the Drosophila embryo.
Opa Protein Structure
It was termed a "pair-rule" gene because embryos lacking opa die during embryogenesis with cuticular patterning defects in every other segment.
Three of these have significant expression in the disc of the eye antenna, which will form the adult eye, and most of the external structures of the head (Lee et al. 2007). These constructs range from 20 kb upstream of the opa transcription start site to 5 kb downstream (FlyLight project) (Pfeiffer et al. 2008).
Role of opa During Development
- Embryonic Segmentation
- Embryonic Midgut Formation
- Adult Ventral Head Morphogenesis
- opa’s Role in the Drosophila Nervous System
- opa Is Part of the Circadian Clock
The Drosophila BMP, dpp, plays a role in the morphogenesis of the adult ventral head via its expression in the eye-antennal discs (Stultz et al. 2006b). Another GATA family transcription factor, snake, serves a similar purpose in the fly body.
Opa as a Transcription Factor
- Opa Is a Sequence-Specific DNA Binding Protein
- Opa May Not Require DNA Binding to Activate Transcription in All Cases
- Opa Displays Concentration-Dependent Effects
The Ci site and the optimal Opa site with significantly higher affinity than Opa (Sen et al. 2010). They also bind Gli proteins, the final effectors of the Hedgehog pathway (Koyabu et al. 2001).
Summary
Clark E, Akam M (2016) Odd pairs control frequency doubling in Drosophila segmentation by altering the pair rule gene regulatory network. Jurgens G, Wieschaus E, Nussleinvolhard C, Kluding H (1984) Mutations affecting larval cuticle patterning in Drosophila melanogaster.
Zic Genes in Nematodes: A Role in Nervous System Development and Wnt Signaling
Introduction
- Epidermis Development
- Excretory System Development
After terminal division, TTX-3 activates expression of the terminal transcription factor CEH-10 in the postmitotic AIY neuron. REF-2 is expressed in excretory gland cells and is required for the expression of the excretory gland marker lim-6 (Bertrand and Hobert 2009).
Role of REF-2/Zic in Wnt Signaling
The expression of the ttx-3 transcription factor gene is activated in the AIY mother cell (anterior daughter cell), where the Wnt/β- - catenin pathway is inactive, but not in the posterior daughter cell, where the pathway is active. . In addition, Zic factors block the expression of classical target genes of the Wnt/β-catenin pathway in mammalian cell cultures and in Xenopus embryos (Pourebrahim et al. 2011; Fujimi et al. 2012).
Conclusion
Fujimi TJ, Hatayama M, Aruga J (2012) Xenopus Zic3 controls notochord and organizer development through repression of the Wnt/beta-catenin signaling pathway. Nelson FK, Riddle DL (1984) Functional study of the Caenorhabditis elegans secretory-excretory system using laser microsurgery.
Lophotrochozoan Zic Genes
- Lophotrochozoans
- Comparisons of the Expression Patterns of Zic Genes in Polychaete and Oligochaete Annelids
- Annelid Zic Genes
- Comparison of Mesodermal Expression in Oligochaetes and Polychaetes
- Comparisons of Zic Expression in Oligochaete and Polychaete Neural Development
- Zic Expression in Brachiopods
- Dicyemid Zic Genes
- Roles of Zic Genes in Planarian Head Regeneration
- Summary of the Lophotrochozoan Zic Genes
Notum is required for head regeneration and is expressed at the anterior pole (Petersen and Reddien 2011). On the anterior side of wounds, zic1 expression in stem cells (neoblast) is induced by the secretory inhibitor of wnt signaling (notum).
Ascidian Zic Genes
- Two Zic-Related Genes in Ascidian Genomes .1 Ascidians
- Zic Genes
- Expression Pattern and Function of Zic-r.a
- Expression and Function of Maternal Zic-r.a
- Expression in the Nervous System
- Expression Pattern and Function of Zic-r.b
- Expression and Function at the 32-Cell Stage
- Expression and Functions at the Gastrula Stage
- Conclusions
Zic-r.b and Tbx6.b activate Mrf (the only ortholog for vertebrate MyoD, Myf5, Myogenin and Mrf4, as described above) (Imai et al. 2006). At the 32-cell stage, Zic-r.b begins to be expressed in the marginal cells of the vegetative hemisphere.
Amphibian Zic Genes
Introduction
- Experimental Approaches Unique to Xenopus
- Ectodermal Explants (Animal Caps)
- Keller Explants
The hGR domain forms a complex with endogenous HSP90 and thus retains the transcription factor in the cytoplasm (Kolm and Sive 1995; Mattioni et al. 1994). This system demonstrated that calcium transients are required for induction of zic3 expression (Leclerc et al. 2003).
Zic Family Genes and Their Expression in Xenopus Embryos
- Comparison of Zic Genes in the Allotetraploid Genome of Xenopus laevis
- Expression of Zic Genes in Xenopus Embryos
- Blastula Embryos
- Gastrula Embryos
- Neurula Embryos
- Tailbud Stage Embryos
During neurula (stage 14), zic1-3 are expressed in the neural plate and to some extent in the notochord (Reprinted from Fujimi et al. 2012 with permission from the publisher). Between the neurula (stages 15 and 19) and the tail bud (stages 23 and later stages), all zic genes are expressed in the dorsal neural tube.
Upstream Regulators of Zic Gene Expression
- Inhibition of BMP Signaling
- Siamois and Twin
- Calcium Signaling
- FGF Signaling
- Wnt Signaling
- FoxD4 and Other Factors
A dominant interfering Smad is able to induce expression of zic1 in the absence of translation (Marchal et al. 2009), indicating direct regulation. A regulator of zic gene expression in the early neural ectoderm is the forkhead transcription factor FoxD4 (also called FoxD5), which is expressed in tissue destined to become the neural ectoderm (Yan et al. 2009).
Direct Transcriptional Targets of Zic Proteins
- Screens for Zic1 Direct Targets in Xenopus
- Direct Targets of Zic1 During Early Neurula Stages
- Xfeb (Glipr2)
- VegT, Eomesodermin, and myoD Are Transcription Factors Important for Mesoderm Development
- Other direct targets of Zic1
- Neural Crest-Specific Direct Targets of Zic1
- Interaction with Other Proteins
A large number of genes were identified in a screen for direct targets of Zic1 during neural plate development (Cornish et al. 2009). The transcription factor sall1 is expressed in the midbrain and in the posterior regions of the neural plate (Hollemann et al. 1996).
Biological Roles of Zic Transcription Factors
- Role of Maternally Expressed Zic2
- Zic Genes During Gastrulation and Early Patterning of Xenopus Embryos
- Zic Proteins and Wnt Signaling
- Zic Genes During Patterning of the Neural Plate
- Zic Genes and the Neural Crest
- Zic Genes and the Proliferation and Differentiation of Cells in the Nervous System
In Xenopus, all members of the zic family are expressed in the border region of the neural plate (Figure 7.2; Fujimi et al. 2006) and are important for neural crest cell formation. The expression of zic1 and pax3 overlaps in the putative neural crest region (Sato et al. 2005; Hong and Saint-Jeannet 2007).
Xenopus Studies Contribute to Our Understanding of Human Diseases
It directly induces zic2 transcription while indirectly repressing zic1 and zic3 expression (Neilson et al. 2012;. The ZIC1 and engrailed (EN1) gene expression domains overlap in the developing sutures (Twigg et al. 2015).
Conclusion
Zic3 plays a role in the formation of the left-right axis and induction of the neural crest (Cast et al. Kitaguchi T, Nagai T, Nakata K, Aruga J, Mikoshiba K (2000) Zic3 is involved in left-right specification by Xenopus Foster.
- Genomic Organization and Protein Structure of Medaka zic Genes
- The Expression Patterns of Medaka zic Genes
- The Function of zic1/zic4 in the Somite: Insights from Medaka Double anal fin (Da) Mutant
- Embryonic Phenotypes
- Adult Phenotypes
- Transcriptional Regulation of zic1/zic4 .1 Regulatory Elements of zic1/zic4
- Two Distinct Modes of Regulation of zic1/zic4 Transcription
- zic1/zic4 Function in DV Patterning Is Conserved in Vertebrates
- Evolution of zic Dorsal Expression in the Vertebrate Somite
- zic1 and zic4 in the Trunk and Implications for Human Congenital Defects
- Conclusions and Future Perspectives
Tohyama et al. 2011), which may be related to the abnormal expression of zic1 and zic4 in the trunk region. Studies using medaka showed that zic1/zic4 in dorsal somites regulate the dorsal-specific external morphology of the trunk region.
Zebrafish Zic Genes Mediate Developmental Signaling
Introduction
They are characterized by the presence of a Zn finger DNA-binding domain of the C2H2 type, which is highly similar to that of the Gli family proteins (Aruga et al. 1994). Their physical interactions with Gli proteins, as well as their ability to bind the Gli consensus motif (Mizugishi et al. 2001), suggested an interaction with the Hh signaling pathway.
The Zebrafish Zic Family of Transcription Factors
This idea is supported by similarities in spatiotemporal expression patterns and somewhat overlapping functions between pairs of zic genes (Inoue et al. The role of Zic genes during neuronal development is conserved in all organisms that have a nervous system (Lindgens et al. 2004), suggesting , that these genes play an important role in the development and evolution of the nervous system.
Zic3 as a Transcription Factor
Some of these enhancers form large regulatory regions up to 50 kb previously termed “super enhancers” (Whyte et al. 2013). Finally, genome-wide analysis of Zic3 binding sites showed that almost half of all Zic3 binding sites contain both Zic3 and Gli motifs (Winata et al. 2013).
Zic3 and Global Regulation of Development
The example of Zic3 illustrates this principle—most Zic3 binding sites are surrounded by poorly conserved regions, which may indicate different compositions of multiprotein complexes that bind to target CREs, resulting in evolutionary diversification. This could be seen not only due to a genome-wide shift in Zic3 binding mode.
Zic3 in Gastrulation and Left-Right (L-R) Patterning
Defects in the midline structures are associated with aberrations in the L-R pattern (Danos and Yost 1996; Bisgrove et al. 2000). This example serves as an illustration of the diversity of Zic3 developmental functions (Winata et al. 2013).
Zic Genes in Neural Development
- Zic and Neural Crest
- Zic and Neurulation
- Zic and Roof Plate
- Zic and Midbrain
- Zic and Hindbrain
- Zic and Disease
Such extension of the roof plate may allow a long-distance transport of dorsal Wnts (Kondrychyn et al. 2013). In the hindbrain, a similar regulatory module functions downstream of Zic2a and Zic2b to regulate the patterning of hindbrain motor neurons (Drummond et al. 2013).
Conclusions
Grinblat Y, Sive H (2001) Zic gene expression marks anteroposterior patterning in the presumptive neurectoderm of the zebrafish gastrula. Ungar AR, Kelly GM, Moon RT (1995) Wnt4 affects morphogenesis when misexpressed in the zebrafish embryo.
Overview of Rodent Zic Genes
- Discovery of the Murine Zic Genes
- The Genomic Arrangement and Sequence of the Rodent Zic Genes
- The Structure and Conservation of the Murine ZIC Proteins
- Intrinsic Disorder in the ZIC Proteins
- Gene Expression
- Biological Function of the Murine Zic Genes
- Redundant Zic Gene Function
This mutation reduces protein stability and disrupts nuclear localization of the protein (Chhin et al. 2007). IUPred (Dosztányi et al. 2005) was used to predict disorder within each of the five mouse ZIC proteins.
