Human Molecular Genetics Advance Access published online on July 9, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn197
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Zic2-associated holoprosencephaly is caused by a transient defect in the organiser region during gastrulation
1 Early Development, Mammalian Genetics Unit, MRC Harwell, Oxfordshire, OX11 0RD, UK 2 Molecular Embryology, Mammalian Genetics Unit, MRC Harwell, Oxfordshire, OX11 0RD, UK 3 ARC Special Research Centre for the Molecular Genetics of Development and Molecular Genetics and Evolution Group, Research School of Biological Sciences, The Australian National University, Canberra, ACT, 2601, Australia
* Author for correspondence: Molecular Genetics and Evolution Group, Research School of Biological Sciences, The Australian National University, Canberra, ACT, 2601, Australia Tel: +61 (0)2 6125 9158 Fax: +61 (0)2 6125 8294 e-mail: ruth.arkell{at}anu.edu.au
Received April 24, 2008; Revised July 8, 2008; Accepted July 8, 2008
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 signaling. 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 able to account for the HPE phenotype are present in Zic2 mutants before the onset of Shh signaling. Mutation of Zic2 causes HPE via a transient defect in the function of the organiser 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 organiser formation and that the PCP develops via a multi-step process.
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