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Jun Aruga - One of the best experts on this subject based on the ideXlab platform.

  • an evolutionarily conserved mesodermal enhancer in vertebrate zic3
    Scientific Reports, 2018
    Co-Authors: Yuri S Odaka, Jun Aruga, Atsushi Toyoda, Takahide Tohmonda
    Abstract:

    Zic3 encodes a zinc finger protein essential for the development of meso-ectodermal tissues. In mammals, Zic3 has important roles in the development of neural tube, axial skeletons, left-right body axis, and in maintaining pluripotency of ES cells. Here we characterized cis-regulatory elements required for Zic3 expression. Enhancer activities of human-chicken-conserved noncoding sequences around Zic1 and Zic3 were screened using chick whole-embryo electroporation. We identified enhancers for meso-ectodermal tissues. Among them, a mesodermal enhancer (Zic3-ME) in distant 3' flanking showed robust enhancement of reporter gene expression in the mesodermal tissue of chicken and mouse embryos, and was required for mesodermal Zic3 expression in mice. Zic3-ME minimal core region is included in the DNase hypersensitive region of ES cells, mesoderm, and neural progenitors, and was bound by T (Brachyury), Eomes, Lef1, Nanog, Oct4, and ZIC2. Zic3-ME is derived from an ancestral sequence shared with a sequence encoding a mitochondrial enzyme. These results indicate that Zic3-ME is an integrated cis-regulatory element essential for the proper expression of Zic3 in vertebrates, serving as a hub for a gene regulatory network including Zic3.

  • zic1 function in normal cerebellar development and human developmental pathology
    Advances in Experimental Medicine and Biology, 2018
    Co-Authors: Jun Aruga, Kathleen J Millen
    Abstract:

    Zic genes are strongly expressed in the cerebellum. This feature leads to their initial identification and their name “zic,” as the abbreviation of “zinc finger protein of the cerebellum.” Zic gene function in cerebellar development has been investigated mainly in mice. However, association of heterozygous loss of ZIC1 and ZIC4 with Dandy-Walker malformation, a structural birth defect of the human cerebellum, highlights the clinical relevance of these studies. Two proposed mechanisms for Zic-mediated cerebellar developmental control have been documented: regulation of neuronal progenitor proliferation-differentiation and the patterning of the cerebellar primordium. Clinical studies have also revealed that ZIC1 gain of function mutations contribute to coronal craniosynostosis, a rare skull malformation. The molecular pathways contributing to these phenotypes are not fully explored; however, embryonic interactions with sonic hedgehog signaling, retinoic acid signaling, and TGFβ signaling have been described during mouse cerebellar development. Further, Zic1/2 target a multitude of genes associated with cerebellar granule cell maturation during postnatal mouse cerebellar development.

  • Link between the causative genes of holoprosencephaly: ZIC2 directly regulates Tgif1 expression
    Nature Publishing Group, 2018
    Co-Authors: Akira Ishiguro, Minoru Hatayama, Maky I. Otsuka, Jun Aruga
    Abstract:

    Abstract One of the causal genes for holoprosencephaly (HPE) is ZIC2 (HPE5). It belongs to the zinc finger protein of the cerebellum (Zic) family of genes that share a C2H2-type zinc finger domain, similar to the GLI family of genes. In order to clarify the role of ZIC2 in gene regulation, we searched for its direct target genes using chromatin immunoprecipitation (ChIP). We identified TGIF1 (HPE4), another holoprosencephaly-causative gene in humans. We identified ZIC2-binding sites (ZBS) on the 5′ flanking region of Tgif1 by in vitro DNA binding assays. ZBS were essential for ZIC2-dependent transcriptional activation in reporter gene assays. ZIC2 showed a higher affinity to ZBS than GLI-binding sequences. ZIC2-binding to the cis-regulatory element near the Tgif1 promoter may be involved in the mechanism underlying forebrain development and incidences of HPE

  • RESEARCH ARTICLE Open Access Expression of ZIC family genes in meningiomas and other brain tumors
    2013
    Co-Authors: Jun Aruga, Yayoi Nozaki, Minoru Hatayama, Yuri S Odaka, Naoki Yokota
    Abstract:

    Background: Zic zinc finger proteins are present in the developing rodent meninges and are required for cell proliferation and differentiation of meningeal progenitors. Although human ZIC genes are known to be molecular markers for medulloblastomas, their expression in meningioma has not been addressed to date. Methods: We examined the mRNA and protein expression of human ZIC1, ZIC2, ZIC3, ZIC4 and ZIC5 genes in meningiomas in comparison to other brain tumors, using RT-PCR, analysis of published microarray data, and immunostaining. Results: ZIC1, ZIC2 and ZIC5 transcript levels in meningiomas were higher than those in whole brain or normal dura mater, whereas all five ZIC genes were abundantly expressed in medulloblastomas. The expression level of ZIC1 in public microarray data was greater in meningiomas classified as World Health Organization Grade II (atypical) than those classified as Grade I (benign). Immunoscreening using anti-ZIC antibodies revealed that 23 out of 23 meningioma cases were ZIC1/2/3/5-immunopositive. By comparison, nuclear staining by the anti-ZIC4 antibody was not observed in any meningioma case, but was strongly detected in all four medulloblastomas. ZICpositive meningiomas included meningothelial, fibrous, transitional, and psammomatous histological subtypes. In normal meninges, ZIC-like immunoreactivities were detected in vimentin-expressing arachnoid cells both in huma

  • xenopus zic3 controls notochord and organizer development through suppression of the wnt β catenin signaling pathway
    Developmental Biology, 2012
    Co-Authors: Takahiko J Fujimi, Minoru Hatayama, Jun Aruga
    Abstract:

    Zic3 controls neuroectodermal differentiation and left-right patterning in Xenopus laevis embryos. Here we demonstrate that Zic3 can suppress Wnt/β-catenin signaling and control development of the notochord and Spemann's organizer. When we overexpressed Zic3 by injecting its RNA into the dorsal marginal zone of 2-cell-stage embryos, the embryos lost mesodermal dorsal midline structures and showed reduced expression of organizer markers (Siamois and Goosecoid) and a notochord marker (Xnot). Co-injection of Siamois RNA partially rescued the reduction of Xnot expression caused by Zic3 overexpression. Because the expression of Siamois in the organizer region is controlled by Wnt/β-catenin signaling, we subsequently examined the functional interaction between Zic3 and Wnt signaling. Co-injection of Xenopus Zic RNAs and β-catenin RNA with a reporter responsive to the Wnt/β-catenin cascade indicated that Zic1, ZIC2, Zic3, Zic4, and Zic5 can all suppress β-catenin-mediated transcriptional activation. In addition, co-injection of Zic3 RNA inhibited the secondary axis formation caused by ventral-side injection of β-catenin RNA in Xenopus embryos. Zic3-mediated Wnt/β-catenin signal suppression required the nuclear localization of Zic3, and involved the reduction of β-catenin nuclear transport and enhancement of β-catenin degradation. Furthermore, Zic3 co-precipitated with Tcf1 (a β-catenin co-factor) and XIC (I-mfa domain containing factor required for dorsoanterior development). The findings in this report produce a novel system for fine-tuning of Wnt/β-catenin signaling.

Katsuhiko Mikoshiba - One of the best experts on this subject based on the ideXlab platform.

  • zic deficiency in the cortical marginal zone and meninges results in cortical lamination defects resembling those in type ii lissencephaly
    The Journal of Neuroscience, 2008
    Co-Authors: Takashi Inoue, Katsuhiko Mikoshiba, Masaharu Ogawa, Jun Aruga
    Abstract:

    The formation of the highly organized cortical structure depends on the production and correct placement of the appropriate number and types of neurons. The Zic family of zinc-finger transcription factors plays essential roles in regulating the proliferation and differentiation of neuronal progenitors in the medial forebrain and the cerebellum. Examination of the expression of Zic genes demonstrated that Zic1, ZIC2, and Zic3 were expressed by the progenitor cells in the septum and cortical hem, the sites of generation of the Cajal-Retzius (CR) cells. Immunohistochemical studies have revealed that Zic proteins were abundantly expressed in the meningeal cells and that the majority of the CR cells distributed in the medial and dorsal cortex also expressed Zic proteins in the mid-late embryonic and postnatal cortical marginal zones. During embryonic cortical development, Zic1/Zic3 double-mutant and hypomorphic ZIC2 mutant mice showed a reduction in the number of CR cells in the rostral cortex, whereas the cell number remained unaffected in the caudal cortex. These mutants also showed mislocalization of the CR cells and cortical lamination defects, resembling the changes noted in type II (cobblestone) lissencephaly, throughout the brain. In the Zic1/3 mutant, reduced proliferation of the meningeal cells was observed before the thinner and disrupted organization of the pial basement membrane (BM) with reduced expression of the BM components and the meningeal cell-derived secretory factor. These defects correlated with the changes in the end feet morphology of the radial glial cells. These findings indicate that the Zic genes play critical roles in cortical development through regulating the proliferation of meningeal cells and the pial BM assembly.

  • ZIC2 and zic3 synergistically control neurulation and segmentation of paraxial mesoderm in mouse embryo
    Developmental Biology, 2007
    Co-Authors: Takashi Inoue, Katsuhiko Mikoshiba, Jun Aruga
    Abstract:

    Abstract Zic family zinc-finger proteins play various roles in animal development. In mice, five Zic genes (Zic1–5) have been reported. Despite the partly overlapping expression profiles of these genes, mouse mutants for each Zic show distinct phenotypes. To uncover possible redundant roles, we characterized ZIC2/Zic3 compound mutant mice. ZIC2 and Zic3 are both expressed in presomitic mesoderm, forming and newly generated somites with differential spatiotemporal accentuation. Mice heterozygous for the hypomorphic ZIC2 allele together with null Zic3 allele generally showed severe malformations of the axial skeleton, including asymmetric or rostro-caudally bridged vertebrae, and reduction of the number of caudal vertebral bones, that are not obvious in single mutants. These defects were preceded by perturbed somitic marker expression, and reduced paraxial mesoderm progenitors in the primitive streak. These results suggest that ZIC2 and Zic3 cooperatively control the segmentation of paraxial mesoderm at multiple stages. In addition to the segmentation abnormality, the compound mutant also showed neural tube defects that ran the entire rostro-caudal extent (craniorachischisis), suggesting that neurulation is another developmental process where ZIC2 and Zic3 have redundant functions.

  • zic1 and zic3 regulate medial forebrain development through expansion of neuronal progenitors
    The Journal of Neuroscience, 2007
    Co-Authors: Takashi Inoue, Katsuhiko Mikoshiba, Maya Ota, Miyuki Ogawa, Jun Aruga
    Abstract:

    The medial telencephalon is a source of neurons that follow distinct tangential trajectories of migration to various structures such as the cerebral cortex, striatum, and olfactory bulb. In the present study, we characterized the forebrain anomalies in Zic1/Zic3 compound mutant mice. Zic1 and Zic3 were strongly expressed in the medial structures, including the septum, medial cerebral cortex, and choroid plexus. Mice homozygous for the Zic1 mutant allele together with the null Zic3 allele showed medial forebrain defects, which were not obvious in either Zic1 or Zic3 single mutants. Absence of both Zic1 and Zic3 caused hypoplasia of the hippocampus, septum, and olfactory bulb. Analysis of the cell cycle revealed that the cell cycle exit rate was increased in the septa of double mutants. Misexpression of Zic3 in the ventricular layer of the cerebral cortex inhibited neuronal differentiation. These results indicated that both Zic1 and Zic3 function in maintaining neural precursor cells in an undifferentiated state. The functions of these genes may be essential to increasing neural cell numbers regionally in the medial telencephalon and to proper mediolateral patterning of the telencephalon.

  • ZIC2 dependent transcriptional regulation is mediated by dna dependent protein kinase poly adp ribose polymerase and rna helicase a
    Journal of Biological Chemistry, 2007
    Co-Authors: Akira Ishiguro, Katsuhiko Mikoshiba, Maki Ideta, David J Chen, Jun Aruga
    Abstract:

    The Zic family of zinc finger proteins is essential for animal development, as demonstrated by the holoprosencephaly caused by mammalian ZIC2 mutation. To determine the molecular mechanism of Zic-mediated developmental control, we characterized two types of high molecular weight complexes, including ZIC2. Complex I was composed of DNA-dependent protein kinase catalytic subunit (DNA-PKcs), Ku70/80, and poly(ADP-ribose) polymerase; complex II contained Ku70/80 and RNA helicase A; all the components interacted directly with ZIC2 protein. Immunoprecipitation, subnuclear localization, and in vitro phosphorylation analyses revealed that the DNA-PKcs in complex I played an essential role in the assembly of complex II. Stepwise exchange from complex I to complex II depended on phosphorylation of ZIC2 by DNA-PK and poly-(ADP-ribose) polymerase. Phosphorylated ZIC2 protein made a stable complex with RNA helicase A, and complex II could interact with RNA polymerase II. Phosphorylation-dependent transformation of ZIC2-containing molecular complexes may occur in transcriptional regulation.

  • myogenic repressor i mfa interferes with the function of zic family proteins
    Biochemical and Biophysical Research Communications, 2004
    Co-Authors: Kiyomi Mizugishi, Katsuhiko Mikoshiba, Minoru Hatayama, Takashi Inoue, Takahide Tohmonda, Miyuki Ogawa, Jun Aruga
    Abstract:

    Zinc finger proteins belonging to the Zic family control several developmental processes such as patterning of the axial skeleton. Here we mapped the transcriptional regulatory domains in ZIC2 protein and identified a protein which specifically binds to one of them. In the mapping experiments, an amino-terminal region was identified as transcriptional regulatory domains. A search for proteins binding to the amino terminal domain of ZIC2 revealed that inhibitor of MyoD family (I-mfa) protein, which has been identified as a repressor of myogenic helix-loop-helix class transcription factors, can physically interact with the amino terminal domain. When Zic1-3 and I-mfa proteins were co-expressed in cultured cells, nuclear import of the Zic proteins was inhibited. Consequently, I-mfa inhibited transcriptional activation by the Zic proteins in cultured cells. These results suggest that the physical and functional interaction between Zic and I-mfa proteins can play a role in the vertebrate development.

Ruth M Arkell - One of the best experts on this subject based on the ideXlab platform.

  • ZIC2 in holoprosencephaly
    Advances in Experimental Medicine and Biology, 2018
    Co-Authors: Kristen S. Barratt, Ruth M Arkell
    Abstract:

    The ZIC2 transcription factor is one of the most commonly mutated genes in Holoprosencephaly (HPE) probands. HPE is a severe congenital defect of forebrain development which occurs when the cerebral hemispheres fail to separate during the early stages of organogenesis and is typically associated with mispatterning of the embryonic midline. Recent study of genotype-phenotype correlations in HPE cases has defined distinctive features of ZIC2-associated HPE presentation and genetics, revealing that ZIC2 mutation does not produce the craniofacial abnormalities generally thought to characterise HPE but leads to a range of non-forebrain phenotypes. Furthermore, the studies confirm the extent of ZIC2 allelic heterogeneity and that pathogenic variants of ZIC2 are associated with both classic and middle interhemispheric variant (MIHV) HPE which arise from defective ventral and dorsal forebrain patterning, respectively. An allelic series of mouse mutants has helped to delineate the cellular and molecular mechanisms by which one gene leads to defects in these related but distinct embryological processes.

  • ZIC2 mutation causes Holoprosencephaly via disruption of NODAL signalling
    Human molecular genetics, 2016
    Co-Authors: Rob Houtmeyers, Olive Tchouate Gainkam, Hannah A Glanville-jones, Ben Van Den Bosch, Anna Chappell, Kristen S. Barratt, Jacob Souopgui, Sabine Tejpar, Ruth M Arkell
    Abstract:

    The ZIC2 transcription factor is one of the genes most commonly mutated in Holoprosencephaly (HPE) probands. Studies in cultured cell lines and mice have shown a loss of ZIC2 function is the pathogenic mechanism but the molecular details of this ZIC2 requirement remain elusive. HPE arises when signals that direct morphological and fate changes in the developing brain and facial primordia are not sent or received. One critical signal is sent from the prechordal plate (PrCP) which develops beneath the ventral forebrain. An intact NODAL signal transduction pathway and functional ZIC2 are both required for PrCP establishment. We now show that ZIC2 acts downstream of the NODAL signal during PrCP development. ZIC2 physically interacts with SMAD2 and SMAD3, the receptor activated proteins that control transcription in a NODAL dependent manner. Together SMAD3 and ZIC2 regulate FOXA2 transcription in cultured cells and ZIC2 also controls the foxA2 expression during Xenopus development. Variant forms of the ZIC2 protein, associated with HPE in man or mouse, are deficient in their ability to influence SMAD-dependent transcription. These findings reveal a new mechanism of NODAL signal transduction in the mammalian node and provide the first molecular explanation of how ZIC2 loss-of-function precipitates HPE.

  • ZIC2 associated holoprosencephaly is caused by a transient defect in the organizer region during gastrulation
    Human Molecular Genetics, 2008
    Co-Authors: Nicholas Warr, Anna Chappell, Nicola Powlesglover, Joan Robson, Dominic P Norris, Ruth M Arkell
    Abstract:

    The putative transcription factor ZIC2 is associated with a defect of forebrain development, known as Holoprosencephaly (HPE), in humans and mouse, yet the mechanism by which aberrant ZIC2 function causes classical HPE is unexplained. The zinc finger domain of all mammalian Zic genes is highly homologous with that of the Gli genes, which are transcriptional mediators of Shh signalling. Mutations in Shh and many other Hh pathway members cause HPE and it has been proposed that ZIC2 acts within the Shh pathway to cause HPE. We have investigated the embryological cause of ZIC2-associated HPE and the relationship between ZIC2 and the Shh pathway using mouse genetics. We show that ZIC2 does not interact with Shh to produce HPE. Moreover, molecular defects that are able to account for the HPE phenotype are present in ZIC2 mutants before the onset of Shh signalling. Mutation of ZIC2 causes HPE via a transient defect in the function of the organizer region at mid-gastrulation which causes an arrest in the development of the prechordal plate (PCP), a structure required for forebrain midline morphogenesis. The analysis provides genetic evidence that ZIC2 functions during organizer formation and that the PCP develops via a multi-step process.

  • in vitro analysis of partial loss of function ZIC2 mutations in holoprosencephaly alanine tract expansion modulates dna binding and transactivation
    Human Molecular Genetics, 2005
    Co-Authors: Lucia Y Brown, Ruth M Arkell, Melinda Paraso, Stephen Brown
    Abstract:

    Heterozygous loss-of-function mutations in ZIC2 result in the severe brain malformation known as holoprosencephaly (HPE), indicating that forebrain development is exquisitely sensitive to the activity of this poorly understood transcription factor. To identify the regions of ZIC2 that are essential for activity, we have assessed the ability of a variety of ZIC2 mutant proteins to function in in vitro assays. Two sources of information were used to design relevant mutations. First, phenotype producing mutations in human and in mouse ZIC2 were mimicked and secondly, a comparative sequence analysis of the C-terminal was carried out. Analysis of these mutations suggests that either a decrease or an increase in ZIC2 mediated transcriptional activity can produce a forebrain phenotype. In addition, the analysis reveals that the C-terminal of ZIC2 contains both activation and repression domains. This region of ZIC2 contains an alanine-tract, and expansion of this domain is associated with HPE. In vitro analysis of proteins with alterations in alanine-tract length illustrates that the C-terminal alanine-tract of ZIC2 influences the strength of DNA binding and alters transcriptional activity in a promoter-specific manner. This finding provides a possible mechanism by which alanine-tract expansion mutations could alter the function of other transcription factors.

  • overlapping and distinct expression domains of ZIC2 and zic3 during mouse gastrulation
    Gene Expression Patterns, 2004
    Co-Authors: Paul Elms, Andrew Scurry, Jennifer Davies, Catherine Willoughby, Terry Hacker, Debora Bogani, Ruth M Arkell
    Abstract:

    The Zic genes are the vertebrate homologues of the Drosophila Odd-paired gene. Mutations in two of these genes are associated with human congenital genetic disorders. Mutation of human and mouse ZIC2 is associated with holoprosencephaly which is caused by a defect of ventral forebrain development and mutation of human and mouse Zic3 is associated with a X-linked heterotaxy syndrome that results from a failure of left-right axis formation. The embryological role of the Zic genes in these disorders is not well understood. Here we show that both of these genes are expressed prior to and throughout gastrulation. The genes show some broad similarities in their expression domains. Both genes however are also uniquely expressed in some tissues and these unique domains correlate with regions that potentially play a role in the aetiology of the respective genetic disorders. During primitive streak stages ZIC2 is expressed transiently and uniquely in the node and the head process mesendoderm. The head process is known to be required for the establishment or maintenance of the ventral forebrain, which is the region disrupted in holoprosencephaly. Zic3 is not expressed in the node during primitive streak stages but is expressed in and around the node beginning from the head fold stages of development. This expression of Zic3 correlates well with the first steps in the establishment of the left-right axis. We also examined the expression of the closely related gene, Zic1, and did not detect any transcripts in gastrulation stage embryos.

Stephen Brown - One of the best experts on this subject based on the ideXlab platform.

  • duplication of the ZIC2 gene is not associated with holoprosencephaly
    American Journal of Medical Genetics Part A, 2012
    Co-Authors: Vaidehi Jobanputra, Stephen Brown, Alanna Teatom Burke, Anyane Yeboa Kwame, Anita Shanmugham, Maryam Shirazi, Peter E Warburton, Brynn Levy, Dorothy Warburton
    Abstract:

    Cytogenetic testing using genomic microarrays presents a clinical challenge when data regarding the phenotypic consequences of the genomic alteration are not available. We describe a chromosome 13q32.3 duplication discovered by microarray testing in a fetus with a prenatally detected apparently balanced de novo translocation 46,XY,t(2;13)(q37;q32). Microarray analysis on the fetal DNA showed duplications of 384 kb and 564 kb at the breakpoint regions on chromosomes 2q37.3 and 13q32.3, respectively. There were no disease-associated genes in the duplicated region on chromosome 2q37. The duplicated region on chromosome 13q contains the ZIC2 gene. Haploinsufficiency of ZIC2 is known to cause holoprosencephaly and other brain malformations. Studies in the mouse models have suggested that over expression of ZIC2 may also lead to brain malformations. Fetal MRI of the brain was normal and the family elected to continue the pregnancy. An apparently normal baby was born at term. At 3 months of age a physical exam showed no abnormalities and no developmental delay. This report shows that duplication of ZIC2 is not necessarily associated with brain malformations. We also describe the phenotype from four additional patients with duplications of the region of chromosome 13 containing ZIC2 and three previously described patients with supernumerary marker chromosomes derived from distal chromosome 13. None of the eight patients had holoprosencephaly or brain malformations, indicating that duplication of ZIC2 is not associated with brain anomalies. This information will be useful for counseling in other occurrences of this duplication identified by microarray.

  • ZIC2 is expressed in pluripotent cells in the blastocyst and adult brain expression overlaps with makers of neurogenesis
    Gene Expression Patterns, 2009
    Co-Authors: L Brown, Stephen Brown
    Abstract:

    Members of the zic family of transcription factors are widely understood to act during neural patterning and neural crest development. In particular, studies in mice and humans have shown that ZIC2 has a role in forebrain patterning, while studies in Xenopus and zebrafish have shown that ZIC2 acts during gastrulation. Expression of ZIC2 prior to gastrulation has not been reported in the mouse. In the adult, ZIC2 is known to be strongly expressed in cerebellar granule cells, but expression elsewhere in the adult brain has not been reported. We present data showing that ZIC2 is expressed in pluripotent cells during very early mouse development. Further, in the adult brain, ZIC2 expression is broad and overlaps with markers of neurogenesis. The presence of ZIC2 in pluripotent cells of the embryo as well as in dividing neural cells in the adult suggests that this transcription factor may have a role in maintaining pluripotency.

  • in vitro analysis of partial loss of function ZIC2 mutations in holoprosencephaly alanine tract expansion modulates dna binding and transactivation
    Human Molecular Genetics, 2005
    Co-Authors: Lucia Y Brown, Ruth M Arkell, Melinda Paraso, Stephen Brown
    Abstract:

    Heterozygous loss-of-function mutations in ZIC2 result in the severe brain malformation known as holoprosencephaly (HPE), indicating that forebrain development is exquisitely sensitive to the activity of this poorly understood transcription factor. To identify the regions of ZIC2 that are essential for activity, we have assessed the ability of a variety of ZIC2 mutant proteins to function in in vitro assays. Two sources of information were used to design relevant mutations. First, phenotype producing mutations in human and in mouse ZIC2 were mimicked and secondly, a comparative sequence analysis of the C-terminal was carried out. Analysis of these mutations suggests that either a decrease or an increase in ZIC2 mediated transcriptional activity can produce a forebrain phenotype. In addition, the analysis reveals that the C-terminal of ZIC2 contains both activation and repression domains. This region of ZIC2 contains an alanine-tract, and expansion of this domain is associated with HPE. In vitro analysis of proteins with alterations in alanine-tract length illustrates that the C-terminal alanine-tract of ZIC2 influences the strength of DNA binding and alters transcriptional activity in a promoter-specific manner. This finding provides a possible mechanism by which alanine-tract expansion mutations could alter the function of other transcription factors.

  • ZIC2 patterns binocular vision by specifying the uncrossed retinal projection
    Cell, 2003
    Co-Authors: Eloisa Herrera, Katsuhiko Mikoshiba, Jun Aruga, Lucia Y Brown, Stephen Brown, Rivka A Rachel, Gul Dolen, Carol A Mason
    Abstract:

    During CNS development, combinatorial expression of transcription factors controls neuronal subtype identity and subsequent axonal trajectory. Regulatory genes designating the routing of retinal ganglion cell (RGC) axons at the optic chiasm to the appropriate hemisphere, a pattern critical for proper binocular vision, have not been identified. Here, we show that the zinc finger transcription factor ZIC2, a vertebrate homolog of the Drosophila gene odd-paired, is expressed in RGCs with an uncrossed trajectory during the period when this subpopulation grows from the ventrotemporal retina toward the optic chiasm. Loss- and gain-of-function analyses indicate that ZIC2 is necessary and sufficient to regulate RGC axon repulsion by cues at the optic chiasm midline. Moreover, ZIC2 expression reflects the extent of binocularity in different species, suggesting that ZIC2 is an evolutionarily conserved determinant of RGCs that project ipsilaterally. These data provide evidence for transcriptional coding of axon pathfinding at the midline.

  • immunolocalization of ZIC2 expression in the developing mouse forebrain
    Gene Expression Patterns, 2003
    Co-Authors: Lucia Y Brown, Andreas H Kottmann, Stephen Brown
    Abstract:

    The Zic genes are a family of zinc finger transcription factors defined by their homology with the Drosophila gene, odd-paired (opa). ZIC2 has a critical role in forebrain development, as is evidenced by the fact that, in both mice and humans, diminished expression results in the severe forebrain malformation known as holoprosencephaly. Published information indicates that ZIC2 expression is most prominent in the dorsal neural tube/spinal cord and in the hindbrain; however, there is no published description of the pattern of expression of ZIC2 in the developing forebrain where the main ZIC2 associated phenotype occurs. Using a ZIC2-specific antiserum, we present new information about the expression of ZIC2 in the developing mouse forebrain. In addition, we show that in sonic hedgehog (Shh) null mice, the expression of ZIC2 is expanded ventrally in some structures while absent in others, suggesting that Shh has a role in regulating the expression of ZIC2.

John Godwin - One of the best experts on this subject based on the ideXlab platform.

  • Sexual Phenotype Differences in ZIC2 mRNA Abundance in the Preoptic Area of a Protogynous Teleost,
    2016
    Co-Authors: Thalassoma Bifasciatum, Mary Beth Hawkins, Katherine Mccaffrey, John Godwin
    Abstract:

    The highly conserved members of the zic family of zinc-finger transcription factors are primarily known for their roles in embryonic signaling pathways and regulation of cellular proliferation and differentiation. This study describes sexual phenotype differences in abundances of ZIC2 mRNA in the preoptic area of the hypothalamus, a region strongly implicated in sexual behavior and function, in an adult teleost, Thalassoma bifasciatum. The bluehead wrasse (Thalassoma bifasciatum) is a valuable model for studying neuroendocrine processes because it displays two discrete male phenotypes, initial phase (IP) males and territorial, terminal phase (TP) males, and undergoes socially-controlled protogynous sex change. Previously generated microarray-based comparisons suggested that ZIC2 was upregulated in the brains of terminal phase males relative to initial phase males. To further explore this difference, we cloned a 727 bp sequence for neural ZIC2 from field-collected animals. Riboprobe-based in situ hybridization was employed to localize ZIC2 signal in adult bluehead brains and assess the relative abundance of brain ZIC2 mRNA across sexual phenotypes. We found ZIC2 mRNA expression was extremely abundant in the granular cells of the cerebellum and widespread in other brain regions including in the thalamus, hypothalamus, habenula, torus semicircularis, torus longitudinalis, medial longitudinal fascicle and telencephalic areas. Quantitative autoradiography and phosphorimaging showed ZIC2 mRNA hybridization signal in the preoptic area of the hypothalamus was significantly higher in terminal phase males relative to both initial phase males and females, and silve

  • sexual phenotype differences in ZIC2 mrna abundance in the preoptic area of a protogynous teleost thalassoma bifasciatum
    PLOS ONE, 2011
    Co-Authors: Katherine A Mccaffrey, Mary Beth Hawkins, John Godwin
    Abstract:

    The highly conserved members of the zic family of zinc-finger transcription factors are primarily known for their roles in embryonic signaling pathways and regulation of cellular proliferation and differentiation. This study describes sexual phenotype differences in abundances of ZIC2 mRNA in the preoptic area of the hypothalamus, a region strongly implicated in sexual behavior and function, in an adult teleost, Thalassoma bifasciatum. The bluehead wrasse (Thalassoma bifasciatum) is a valuable model for studying neuroendocrine processes because it displays two discrete male phenotypes, initial phase (IP) males and territorial, terminal phase (TP) males, and undergoes socially-controlled protogynous sex change. Previously generated microarray-based comparisons suggested that ZIC2 was upregulated in the brains of terminal phase males relative to initial phase males. To further explore this difference, we cloned a 727 bp sequence for neural ZIC2 from field-collected animals. Riboprobe-based in situ hybridization was employed to localize ZIC2 signal in adult bluehead brains and assess the relative abundance of brain ZIC2 mRNA across sexual phenotypes. We found ZIC2 mRNA expression was extremely abundant in the granular cells of the cerebellum and widespread in other brain regions including in the thalamus, hypothalamus, habenula, torus semicircularis, torus longitudinalis, medial longitudinal fascicle and telencephalic areas. Quantitative autoradiography and phosphorimaging showed ZIC2 mRNA hybridization signal in the preoptic area of the hypothalamus was significantly higher in terminal phase males relative to both initial phase males and females, and silver grain analysis confirmed this relationship between phenotypes. No significant difference in abundance was found in ZIC2 signal across phenotypes in the habenula, a brain region not implicated in the control of sexual behavior, or cerebellum.