International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


POSTER 25 - CHARACTERIZATION OF HOLOPROSENCEPHALY IN THE ZIC2KU/KU MUTANT

Warr N, Elms P, Willoughby C, Bogani D, Arkell R

MGU MRC Harwell, Didcot, United Kingdom

Holoprosencephaly (HPE) is a relatively common disorder involving the incomplete development and septation of midline structures in the central nervous system. It has an incidence as high as 1:250 in embryogenesis but only 1:16,000 of live births due to intrauterine lethality. Clinical features vary widely, in the more extreme cases, these may include a single brain ventricle and severe facial anomalies such as cyclopia with a proboscis, a single-nostril nose and cleft lip and in less severe cases mild facial dysmorphia may be observed such as a single front incisor and/or narrowly spaced eyes. A number of genes have been linked to HPE in humans and several are members of the Sonic hedgehog (SHH) and BMP signaling pathways including Sonic hedgehog, Hedgehog-interacting protein, Patched, Smoothened, Gli, Wnt, BMP, Nodal, Smads, One-eyed pinhead, and TG-interacting factor. In addition, mutations in ZIC2, a mammalian gene homologous to the Drosophila pair-rule gene odd-paired, can also give rise to HPE in humans. We have previously isolated and partially characterized a murine Zic2 mutant called kumba (Zic2ku) which has a point mutation in the fourth C2H2 zinc finger domain. Zic2ku/ku homozygotes exhibit holoprosencephaly as well as other developmental defects (heart looping, neural tube closure, hindbrain segmentation and neural crest migration). We have initiated a study into the embryological cause of holoprosencephaly in the Zic2ku/ku mutant using in situ hybridization with probes for midline markers. The preliminary results are presented and the potential interactions between Zic2 and the SHH and/or BMP pathways during forebrain development are discussed.

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