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BAC-mediated gene-dosage analysis reveals a role for Zipro1 (Ru49/Zfp38) in progenitor cell proliferation in cerebellum and skin

Abstract

Genetic analysis in mice has most commonly employed two general strategies: phenotypic screens for spontaneous or induced mutations and genotypic analysis using homologous recombination or gene trapping to produce deletion or insertion mutants. Here we use bacterial artificial chromosome (BAC)-mediated gene-dosage analysis in transgenic mice to reveal novel genetic functions that are not evident from conventional loss-of-function mutations. We demonstrate a role for the zinc-finger transcription factor Zipro1 (formerly Ru49 and Zfp38) in the proliferation of granule cell precursors in the developing cerebellum, and document the contribution of this process to the final stages of cerebellar morphogenesis. We also show that Zipro1 is expressed in skin, and increased Zipro1 dosage results in a hair-loss phenotype associated with increased epithelial cell proliferation and abnormal hair follicle development.

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Figure 1: Targeted disruption of Zipro1.
Figure 2: Schematic drawing and fine restriction mapping of BAC169, BAC169.
Figure 3: Generation of BAC169tRGFP transgenic mice.
Figure 4: Morphological alterations in the BAC169tEGFP transgenic cerebella.
Figure 5: Cell proliferation versus cell death in BAC169tEGFP transgenic mice.
Figure 6: Genetic influence of Zipro1 dosage on the formation of four intralobular fissures in the cerebellum of P20–22 mice (a, b,c,d).
Figure 7: Skin phenotype of Zipro1 transgenic mice versus wild-type mice.

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Acknowledgements

We thank M.E. Hatten for advice regarding the granule cell proliferation assay; P. Mombaerts and S.C. Gong for help in creating the loss-of-function mouse mutant; M.E. Hatten, R.B. Darnell, J. Krueger, Z. Yue and T. Anthony for helpful discussions; and J.P. Walsh for help preparing the manuscript. This work was funded by the Howard Hughes Medical Institute and by NINDS PHS 30532. X.W.Y. was also supported by the NIH MSTP grant GM07739, a grant from the Andrew W. Mellon Foundation.

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Correspondence to Nathaniel Heintz.

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Yang, X., Wynder, C., Doughty, M. et al. BAC-mediated gene-dosage analysis reveals a role for Zipro1 (Ru49/Zfp38) in progenitor cell proliferation in cerebellum and skin. Nat Genet 22, 327–335 (1999). https://doi.org/10.1038/11896

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