Disease relevance of Zic3

• 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 [1].
• While nearly one-fourth of hemizygous Bent tail (Bn/Y, Zic3-deficient) mice developed neural tube defects in their midbrain and hindbrain region, the other Bn/Y mice showed apparently normal behaviour in a C57BL/6 genetic background [2].

High impact information on Zic3

• Overexpression of Zic3 resulted in hyperplastic neural and neural crest derived tissue [3].
• Refined genetic and physical mapping of the BN: critical region demonstrate that the mutation is associated with a <170 kb submicroscopic deletion that includes the anonymous microsatellite marker DXMit208 as well as the entire Zic3 locus [4].
• Here we describe a role for Zic3, a member of the Gli family of zinc finger transcription factors, in the maintenance of pluripotency in ES cells [5].
• Notably, the expression of Nanog, a key pluripotency regulator and repressor of extraembryonic endoderm specification in ES cells, was significantly reduced in Zic3 knockdown cells [5].
• Zic3 is required for maintenance of pluripotency in embryonic stem cells [5].

Biological context of Zic3

• These results indicate a requirement for Zic3 during early embryogenesis prior to cardiac and visceral organ patterning [6].
• Fifty percent of Zic3 null embryos have cardiac looping anomalies at embryonic day 10.5 to 14.5, with ventral looping and sinistral looping as the predominant phenotypes [7].
• The Bent tail mutant mouse was recently shown to lack a submicroscopic part of the X chromosome containing the Zic3 gene, which encodes a zinc-finger protein controlling vertebrate neural development [2].
• Furthermore, an upstream Nodal enhancer is responsive to Zic3 in both Xenopus and mouse [7].
• RESULTS: In our study, we show that the Bent tail deletion is at least 300 kb in size, encompassing a processed pseudogene and a number of expressed sequence tags in addition to Zic3 [8].

Anatomical context of Zic3

• Our findings suggest that Zic1 and Zic2 have essentially the same properties as Zic3 and that the Xenopus Zic family may act cooperatively in the initial phase of neural and neural crest development [9].
• At later stages, deficiency of Zic3 results in abnormal mesoderm allocation [6].
• Analysis of Zic3 function at early embryonic stages shows that it ensures the fidelity of embryonic patterning, including patterning of the anterior visceral endoderm, the initiation of gastrulation, and positioning of the primitive streak [6].
• Mice bearing a null mutation in Zic3 have left-right patterning defects with associated cardiovascular, vertebra/rib, and central nervous system malformations [10].

Regulatory relationships of Zic3

• Here, it is demonstrated that Brachyury is involved in L-R specification of the Xenopus laevis embryo and regulates expression of Zic3, which controls the L-R specification process [11].

Other interactions of Zic3

• For all stages, significant differences in the spatial expression of Zic1, Zic2, and Zic3 were observed [12].
• These results suggest that a role of Brachyury in L-R specification may be the direct regulation of Zic3 expression [11].

Analytical, diagnostic and therapeutic context of Zic3

• Northern blotting and ribonuclease protection showed that Zic2 and Zic3 are expressed in a restricted manner in the cerebellum at the adult stage [13].
• METHODS: We searched the ENSEMBL database for other genes/transcribed sequences in the Bent tail deletion in addition to Zic3, which we confirmed by PCR analysis [8].

References