Molecular basis of Zic proteins-mediated developmental regulation.

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In this research project, we investigated following subjects : 1.Clarification of signal transduction pathway controlling the funtion of Zic proteins. 2.Identification of the transcriptioin-activating domain in Zic proteins. 3.Identification of uncharacterized Zic-binding proteins. 4.Understanding the the regulatory mechanism of the identified protein-protein interactions and their significance in the developmental control. 5.Exploration and analysis of the downstream target genes of Zic proteins. As an achievement of the investigation, we revealed following facts : 1.Zic proteins can phycally and functionally interact with Gli proteins, which are the transcriptional mediator of the Hedgehog signal (Koyabu et al., 2001 ; Mizugishi et al., 2001), 2.Zic1 can activate the Notch signaling as indicated by the gain-of-function analysis of Zic1 in chick and mouse spinal cord (Aruga et al., 2002), 3.Novel transcription activating domains were mapped in the N terminal region and zinc finger domain of Zic2 proteins (Mizugishi et al., in press), 4.Severeal Zic-binding proteins was identified by yeast two hybrid assay. The role of interaction in skeletal morphogenesis was investigated as for one of the newly identified Zic proteins. 5.Candidates of the Zic 1 downstream target genes in the course of cerebellar development were identified by microarray analysis (Hoshino et al., 2004). The microarray analysis was also carried out using other Zic mutant mice. Some of the candidate genes were now cleared to be important in the regulation of neuronal development.