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Human ZIC1 (zinc finger protein of cerebellum 1), one of five homologs of the Drosophila pair-rule gene odd-paired, encodes a transcription factor previously implicated in vertebrate brain development. Heterozygous deletions of ZIC1 and its nearby paralog ZIC4 on chromosome 3q25.1 are associated with Dandy-Walker malformation of the cerebellum, and loss of the orthologous Zic1 gene in the mouse causes cerebellar hypoplasia and vertebral defects. We describe individuals from five families with heterozygous mutations located in the final (third) exon of ZIC1 (encoding four nonsense and one missense change) who have a distinct phenotype in which severe craniosynostosis, specifically involving the coronal sutures, and variable learning disability are the most characteristic features. The location of the nonsense mutations predicts escape of mutant ZIC1 transcripts from nonsense-mediated decay, which was confirmed in a cell line from an affected individual. Both nonsense and missense mutations are associated with altered and/or enhanced expression of a target gene, engrailed-2, in a Xenopus embryo assay. Analysis of mouse embryos revealed a localized domain of Zic1 expression at embryonic days 11.5-12.5 in a region overlapping the supraorbital regulatory center, which patterns the coronal suture. We conclude that the human mutations uncover a previously unsuspected role for Zic1 in early cranial suture development, potentially by regulating engrailed 1, which was previously shown to be critical for positioning of the murine coronal suture. The diagnosis of a ZIC1 mutation has significant implications for prognosis and we recommend genetic testing when common causes of coronal synostosis have been excluded., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

The Zic1 transcription factor plays multiple roles during early development, for example, in patterning the early neural plate and formation of the neural crest, somites, and cerebellum. To identify direct downstream target genes of Zic1, a microarray screen was conducted in Xenopus laevis that identified 85 genes upregulated twofold or more. These include transcription factors, receptors, enzymes, proteins involved in retinoic acid signaling, and an aquaglyceroporin (aqp-3b), but surprisingly no genes known to be involved in cell proliferation. We show that both aqp-3 and aqp-3b were expressed in adult tissues, while during early embryonic development, only aqp-3b was transcribed. During neurula stages, aqp-3b was expressed specifically in the neural folds. This pattern of aqp-3b expression closely resembled that of NF-protocadherin (NFPC), which is involved in cell adhesion and neural tube closure. Aqp-3b may also be involved in neural tube closure, since mammalian Aqp-3 promotes cell migration and proliferation.

The transcription factor Zic1 plays important roles in patterning the neural plate in early vertebrate development. However, few genes that are regulated by Zic1 are known. We have identified a new direct downstream target gene of Zic1 that we have named Xfeb. Xfeb is a member of the pathogenesis-related (PR) protein superfamily and contains five tandem SCP domains. The sequence of Xfeb suggests that it may possess serine protease activity. Xfeb is expressed in the presumptive hindbrain region during neurula stages and in somite tissues later in development. Xfeb represses the hindbrain gene hoxB1 and the anterior neural gene otx2, suggesting that Xfeb is involved in regionalizing the neural plate, possibly by ensuring a posterior expression limit for otx2., ((c) 2006 Wiley-Liss, Inc.)