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Molecular and Cellular Biology, December 2007, p. 8259-8270, Vol. 27, No. 23
0270-7306/07/$08.00+0     doi:10.1128/MCB.00707-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Forkhead Transcription Factor FoxM1 Regulates Mitotic Entry and Prevents Spindle Defects in Cerebellar Granule Neuron Precursors{triangledown} ,{dagger}

Ulrich Schüller,1,4,{ddagger} Qing Zhao,1,{ddagger} Susana A. Godinho,1 Vivi M. Heine,2 René H. Medema,3 David Pellman,1 and David H. Rowitch1,2*

Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts,1 Department of Pediatrics and Institute for Regeneration Medicine, UCSF, San Francisco, California,2 Department of Medical Oncology, University Medical Center, Utrecht, The Netherlands,3 Center for Neuropathology, Ludwig Maximilians University, Munich, Germany4

Received 23 April 2007/ Returned for modification 1 June 2007/ Accepted 7 September 2007

The forkhead transcription factor FoxM1 has been reported to regulate, variously, proliferation and/or spindle formation during the G2/M transition of the cell cycle. Here we define specific functions of FoxM1 during brain development by the investigation of FoxM1 loss-of-function mutations in the context of Sonic hedgehog (Shh)-induced neuroproliferation in cerebellar granule neuron precursors (CGNP). We show that FoxM1 is expressed in the cerebellar anlagen as well as in postnatal proliferating CGNP and that it is upregulated in response to activated Shh signaling. To determine the requirements for FoxM1 function, we used transgenic mice carrying conventional null alleles or conditionally targeted alleles in conjunction with specific Cre recombinase expression in CGNP or early neural precursors driven by Math1 or Nestin enhancers. Although the overall cerebellar morphology was grossly normal, we observed that the entry into mitosis was postponed both in vivo and in Shh-treated CGNP cultures. Cell cycle analysis and immunohistochemistry with antibodies against phosphorylated histone H3 indicated a significant delay in the G2/M transition. Consistent with this, FoxM1-deficient CGNP showed decreased levels of the cyclin B1 and Cdc25b proteins. Furthermore, the loss of FoxM1 resulted in spindle defects and centrosome amplification. These findings indicate that the functions of FoxM1 in Shh-induced neuroproliferation are restricted to the regulation of the G2/M transition in CGNP, most probably through transcriptional effects on target genes such as those coding for B-type cyclins.

* Corresponding author. Mailing address: Department of Pediatrics and Institute for Regeneration Medicine, UCSF, 533 Parnassus Avenue, U503, San Francisco, CA 94143. Phone: (415) 476-7242. Fax: (415) 476-9976. E-mail: rowitchd{at}peds.ucsf.edu

{triangledown} Published ahead of print on 24 September 2007.

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

{ddagger} These authors contributed equally to this work.

Molecular and Cellular Biology, December 2007, p. 8259-8270, Vol. 27, No. 23
0270-7306/07/$08.00+0     doi:10.1128/MCB.00707-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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