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Molecular and Cellular Biology, September 2006, p. 6913-6922, Vol. 26, No. 18
0270-7306/06/$08.00+0     doi:10.1128/MCB.02255-05

Zfp423 Is Required for Normal Cerebellar Development

Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702

Received 23 November 2005/ Returned for modification 24 January 2006/ Accepted 1 May 2006

Zinc finger protein 423 (also known as Ebf-associated zinc finger protein, Ebfaz) binds to and negatively regulates Ebf1, a basic helix-loop-helix transcription factor required for B-cell lineage commitment and olfactory epithelium development. Zfp423 also binds to Smad1/Smad4 in response to Bmp2 signaling. Zfp423 contains 30 Krüppel-like zinc fingers that are organized into discrete clusters; some zinc fingers are used to bind DNA, while others mediate Zfp423's interaction with other signaling proteins such as Ebf1 and Smad1/Smad4. Previously, we showed that Zfp423 is an oncogene whose upregulation following retroviral integration in murine B cells leads to an arrest in B-cell differentiation and the subsequent development of B-cell lymphomas. To study the biological functions of Zfp423 in vivo, we used recombineering and gene targeting to generate mice that carry conditional as well as null alleles of Zfp423. Homozygous Zfp423 null mice are runted and ataxic, the cerebellum is underdeveloped, and the vermis is severely reduced. In the remaining cerebellar structures, the Purkinje cells are poorly developed and mislocalized. In mice carrying a hypomorphic Zfp423 gene trap allele, lacZ expression in the cerebellum correlates with the Purkinje cell layer, suggesting that these phenotypes are a result of a Purkinje cell-intrinsic defect.

Supplemental material for this article may be found at http://mcb.asm.org/.

This article has been cited by other articles:

• Alcaraz, W. A., Gold, D. A., Raponi, E., Gent, P. M., Concepcion, D., Hamilton, B. A. (2006). Zfp423 controls proliferation and differentiation of neural precursors in cerebellar vermis formation. Proc. Natl. Acad. Sci. USA 103: 19424-19429 [Abstract] [Full Text]