Disease relevance of Zic2

• 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].
• Here we show that reduced expression (knockdown) of mouse Zic2 causes neurulation delay, resulting in HPE and spina bifida [2].
• The biochemical properties of this negative-acting factor closely resemble those of the Ku antigen, a human nuclear DNA-binding heterodimer which is the target of autoantibodies in several autoimmune diseases [3].
• Heat shock selectively inhibits ribosomal RNA gene transcription and down-regulates E1BF/Ku in mouse lymphosarcoma cells [4].
• To investigate the involvement of these proteins in DNA fragmentation after ischemia/reperfusion, Ku protein expression was examined before and after transient focal cerebral ischemia (FCI) in mice [5].

High impact information on Zic2

• We conclude that Isl2 specifies RGC laterality by repressing an ipsilateral pathfinding program unique to VTC RGCs and involving Zic2 and EphB1 [6].
• Loss- and gain-of-function analyses indicate that Zic2 is necessary and sufficient to regulate RGC axon repulsion by cues at the optic chiasm midline [7].
• Zic2 patterns binocular vision by specifying the uncrossed retinal projection [7].
• Zic2 regulates the kinetics of neurulation [2].
• DNA-dependent protein kinase (DNA-PK) consists of a heterodimeric protein (Ku) and a large catalytic subunit (DNA-PKcs) [8].

Biological context of Zic2

• Here, we show that the zinc finger transcription factor Zic2, a vertebrate homolog of the Drosophila gene odd-paired, is expressed in RGCs with an uncrossed trajectory during the period when this subpopulation grows from the ventrotemporal retina toward the optic chiasm [7].
• They are very similar to mouse Zic1 and Zic2 in the protein coding region including the zinc finger domain [9].
• Published information indicates that Zic2 expression is most prominent in the dorsal neural tube/spinal cord and in the hindbrain; however, there is no published description of the pattern of expression of Zic2 in the developing forebrain where the main Zic2 associated phenotype occurs [10].
• Interestingly, besides their role in DSB repair, Ku proteins bind to chromosome ends, or telomeres, protecting them from end-to-end fusions [11].
• scid cells are deficient in Ku and replication protein A phosphorylation by the DNA-dependent protein kinase [12].

Anatomical context of Zic2

• However, the disruption of Zic1, a strong homolog of Zic2 that has an overlapping expression pattern, results in cerebellar malformation with no apparent abnormalities in the forebrain or in posterior neuropore closure [13].
• During primitive streak stages Zic2 is expressed transiently and uniquely in the node and the head process mesendoderm [1].
• Both Zic1 and Zic2 are expressed in the precursor cells of the granule neuron and the neurons in cerebellar nuclei [13].
• Additionally Zic2 is required during hindbrain patterning for the normal development of rhombomeres 3 and 5 [14].
• Zic2 is required for neural crest formation and hindbrain patterning during mouse development [14].

Associations of Zic2 with chemical compounds

• Cross-resistance to ionizing radiation in a murine leukemic cell line resistant to cis-dichlorodiammineplatinum(II): role of Ku autoantigen [15].
• The Ku protein binds to DNA ends and other types of discontinuity in double-stranded DNA [16].

Regulatory relationships of Zic2

• Zic2 controls cerebellar development in cooperation with Zic1 [13].

Other interactions of Zic2

• For all stages, significant differences in the spatial expression of Zic1, Zic2, and Zic3 were observed [17].
• Reduced expression of Zic2 in mice results in spina bifida and holoprosencephaly [13].
• The transcription factor Zic2 and guidance receptor EphB1, required by RGCs to project ipsilaterally, colocalize in RGCs distinct from Isl2 RGCs in the ventral-temporal crescent (VTC), the source of ipsilateral projections [6].
• A search for proteins binding to the amino terminal domain of Zic2 revealed that inhibitor of MyoD family (I-mfa) protein, which has been identified as a repressor of myogenic helix-loop-helix class transcription factors, can physically interact with the amino terminal domain [18].

Analytical, diagnostic and therapeutic context of Zic2

• Northern blotting and ribonuclease protection showed that Zic2 and Zic3 are expressed in a restricted manner in the cerebellum at the adult stage [19].
• We examined the expression of Zic1, Zic2, and Zic3 genes in the mouse embryo by means of in situ hybridization [17].
• In resistant cells, electrophoretic mobility shift assays revealed an increased DNA-end binding activity that could be ascribed, by supershifting the retardation complexes with antibodies, to the autoantigen Ku [15].
• Western-blot analysis with antibodies specific for the two subunits of Ku protein showed the absence of p72 subunit after 3 h of heat shock [4].
• Ku itself is probably involved in stabilizing broken DNA ends, bringing them together and preparing them for ligation [16].

References