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Zic3 interacts with distant regulatory elements to regulate zebrafish developmental genes

ABSTRACT: Zic3 regulates early embryonic patterning in vertebrates. Its loss-of-function disrupts gastrulation, left-right patterning, and neurogenesis. We use the zebrafish as a model to study the developmental role of Zic3 in vivo. Using a combination of two genomics approaches – ChIP-seq and microarray, we identified Zic3 targets, which include genes from the Nodal and Wnt pathways, and show for the first time cis-regulation of these genes by Zic3 using in vivo enhancer assay. We uncovered a previously unrecognized link between Zic3 and the non-canonical Wnt pathway in gastrulation and left-right patterning, and identified neural pre-pattern genes as Zic3 targets during the early steps of neural induction. Zic3 preferably binds to distal intergenic regions, some of which contain evolutionarily conserved functional enhancers. Our study establishes the zebrafish as an excellent model for genome-wide study of a transcription factor in vivo.

ORGANISM(S): Danio rerio

PROVIDER: GSE41458 | GEO | 2014/02/27

SECONDARY ACCESSION(S): PRJNA177350

REPOSITORIES: GEO

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Project description:The process that partitions the nascent vertebrate central nervous system into forebrain, midbrain, hindbrain, and spinal cord after neural induction is of fundamental interest in developmental biology, and is known to be dependent on Wnt/beta-catenin signaling at multiple steps. Neural induction specifies neural ectoderm with forebrain character that is subsequently posteriorized by graded Wnt signaling: embryological and mutant analyses have shown that progressively higher levels of Wnt signaling induce progressively more posterior fates. However, the mechanistic link between Wnt signaling and the molecular subdivision of the neural ectoderm into distinct domains in the anteroposterior (AP) axis is still not clear. To better understand how Wnt mediates neural AP patterning, we performed a temporal dissection of neural patterning in response to manipulations of Wnt signaling in zebrafish. We show that Wnt-mediated neural patterning in zebrafish can be divided into three phases: (I) a primary AP patterning phase, which occurs during gastrulation, (II) a mes/r1 (mesencephalon-rhombomere 1) specification and refinement phase, which occurs immediately after gastrulation, and (III) a midbrain-hindbrain boundary (MHB) morphogenesis phase, which occurs during segmentation stages. A major outcome of these Wnt signaling phases is the specification of the major compartment divisions of the developing brain: first the MHB, then the diencephalic-mesencephalic boundary (DMB). The specification of these lineage divisions depends upon the dynamic changes of gene transcription in response to Wnt signaling, which we show primarily involves transcriptional repression or indirect activation. We show that otx2b is directly repressed by Wnt signaling during primary AP patterning, but becomes resistant to Wnt-mediated repression during late gastrulation. Also during late gastrulation, Wnt signaling becomes both necessary and sufficient for expression of wnt8b, en2a, and her5 in mes/r1. We suggest that the change in otx2b response to Wnt regulation enables a transition to the mes/r1 phase of Wnt-mediated patterning, as it ensures that Wnts expressed in the midbrain and MHB do not suppress midbrain identity, and consequently reinforce formation of the DMB. These findings integrate important temporal elements into our spatial understanding of Wnt-mediated neural patterning and may serve as an important basis of a better understanding of neural patterning defects that have implications in human health.

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Zic3 interacts with distant regulatory elements to regulate zebrafish developmental genes

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