Zfp423 is Required for Normal Cerebellar Development

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2006 Sep 1

PMID 16943432

Citations 52

Authors

Soren Warming

Rivka A Rachel

Nancy A Jenkins

Neal G Copeland

Affiliations

Soon will be listed here.

Abstract

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.

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References

Garcia-Dominguez M, Poquet C, Garel S, Charnay P . Ebf gene function is required for coupling neuronal differentiation and cell cycle exit. Development. 2003; 130(24):6013-25. DOI: 10.1242/dev.00840. View

Hansen J, Floss T, Van Sloun P, Fuchtbauer E, Vauti F, Arnold H . A large-scale, gene-driven mutagenesis approach for the functional analysis of the mouse genome. Proc Natl Acad Sci U S A. 2003; 100(17):9918-22. PMC: 187885. DOI: 10.1073/pnas.1633296100. View

Warming S, Suzuki T, Yamaguchi T, Jenkins N, Copeland N . Early B-cell factor-associated zinc-finger gene is a frequent target of retroviral integration in murine B-cell lymphomas. Oncogene. 2004; 23(15):2727-31. DOI: 10.1038/sj.onc.1207452. View

Lewis P, Gritli-Linde A, Smeyne R, Kottmann A, McMahon A . Sonic hedgehog signaling is required for expansion of granule neuron precursors and patterning of the mouse cerebellum. Dev Biol. 2004; 270(2):393-410. DOI: 10.1016/j.ydbio.2004.03.007. View

Rios I, Alvarez-Rodriguez R, Marti E, Pons S . Bmp2 antagonizes sonic hedgehog-mediated proliferation of cerebellar granule neurones through Smad5 signalling. Development. 2004; 131(13):3159-68. DOI: 10.1242/dev.01188. View

Corrales J, Rocco G, Blaess S, Guo Q, Joyner A . Spatial pattern of sonic hedgehog signaling through Gli genes during cerebellum development. Development. 2004; 131(22):5581-90. DOI: 10.1242/dev.01438. View

Justice M, Morse 3rd H, Jenkins N, Copeland N . Identification of Evi-3, a novel common site of retroviral integration in mouse AKXD B-cell lymphomas. J Virol. 1994; 68(3):1293-300. PMC: 236582. DOI: 10.1128/JVI.68.3.1293-1300.1994. View

Hatten M, Heintz N . Mechanisms of neural patterning and specification in the developing cerebellum. Annu Rev Neurosci. 1995; 18:385-408. DOI: 10.1146/annurev.ne.18.030195.002125. View

Lin H, Grosschedl R . Failure of B-cell differentiation in mice lacking the transcription factor EBF. Nature. 1995; 376(6537):263-7. DOI: 10.1038/376263a0. View

10.

Mo R, Freer A, Zinyk D, Crackower M, Michaud J, Heng H . Specific and redundant functions of Gli2 and Gli3 zinc finger genes in skeletal patterning and development. Development. 1997; 124(1):113-23. DOI: 10.1242/dev.124.1.113. View

11.

Wang S, Tsai R, Reed R . The characterization of the Olf-1/EBF-like HLH transcription factor family: implications in olfactory gene regulation and neuronal development. J Neurosci. 1997; 17(11):4149-58. PMC: 6573563. View

12.

Tsai R, Reed R . Cloning and functional characterization of Roaz, a zinc finger protein that interacts with O/E-1 to regulate gene expression: implications for olfactory neuronal development. J Neurosci. 1997; 17(11):4159-69. PMC: 6573535. View

13.

Sigvardsson M, ORiordan M, Grosschedl R . EBF and E47 collaborate to induce expression of the endogenous immunoglobulin surrogate light chain genes. Immunity. 1997; 7(1):25-36. DOI: 10.1016/s1074-7613(00)80507-5. View

14.

Tsai R, Reed R . Identification of DNA recognition sequences and protein interaction domains of the multiple-Zn-finger protein Roaz. Mol Cell Biol. 1998; 18(11):6447-56. PMC: 109231. DOI: 10.1128/MCB.18.11.6447. View

15.

Wallace V . Purkinje-cell-derived Sonic hedgehog regulates granule neuron precursor cell proliferation in the developing mouse cerebellum. Curr Biol. 1999; 9(8):445-8. DOI: 10.1016/s0960-9822(99)80195-x. View

16.

Millet S, Campbell K, Epstein D, Losos K, Harris E, Joyner A . A role for Gbx2 in repression of Otx2 and positioning the mid/hindbrain organizer. Nature. 1999; 401(6749):161-4. DOI: 10.1038/43664. View

17.

Broccoli V, Boncinelli E, Wurst W . The caudal limit of Otx2 expression positions the isthmic organizer. Nature. 1999; 401(6749):164-8. DOI: 10.1038/43670. View

18.

Hentges K, Weiser K, Schountz T, Woodward L, Morse H, Justice M . Evi3, a zinc-finger protein related to EBFAZ, regulates EBF activity in B-cell leukemia. Oncogene. 2004; 24(7):1220-30. DOI: 10.1038/sj.onc.1208243. View

19.

Warming S, Costantino N, Court D, Jenkins N, Copeland N . Simple and highly efficient BAC recombineering using galK selection. Nucleic Acids Res. 2005; 33(4):e36. PMC: 549575. DOI: 10.1093/nar/gni035. View

20.

Wong Q, Ng V, Lin M, Kung H, Chan D, Huang J . Efficient and seamless DNA recombineering using a thymidylate synthase A selection system in Escherichia coli. Nucleic Acids Res. 2005; 33(6):e59. PMC: 1072810. DOI: 10.1093/nar/gni059. View