UC San Diego

The balance between proliferation and differentiation of cells during development requires coordination between many signaling pathways. Zinc finger protein 423 (Zfp423) has been shown to interact with several signaling pathways including Ebfs, BMP/SMAD, RA, and Notch signaling giving it opportunity to be a factor that integrates these pathways. Zfp423 may also regulate other signaling pathways, identification of which would further our understanding of control of when progenitor cells decide to make the switch from proliferating to differentiation. In chapter two, we identify a mutation in Zfp423 in a mouse with cerebellar hypoplasia. We find that Zfp423 promotes proliferation of cerebellar progenitor cells, particularly in the midline granule cell precursors, and is necessary for proper differentiation of Bergmann glia and Purkinje neurons. Two approaches are used to identify interactions with Zfp423. In chapters three and four, we map QTLs that modify the cerebellar phenotype in mice lacking Zfp423. Four significant QTLs are identified, complicated by interactions from other QTLs, suggesting many interactions with Zfp423. The second approach is to compare expression differences between cerebellums with and without Zfp423. We identify a few genes with significant expression changes in the absence of Zfp423 including an increase in expression of Rhbdl3, an activator of EGF, putting the EGF pathway under regulation by Zfp423