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Molecular and Cellular Biology, November 2006, p. 8418-8426, Vol. 26, No. 22
0270-7306/06/$08.00+0     doi:10.1128/MCB.00821-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Rapid Loss of Intestinal Crypts upon Conditional Deletion of the Wnt/Tcf-4 Target Gene c-Myc{triangledown} ,{dagger}

Vanesa Muncan,1 Owen J. Sansom,5 Leon Tertoolen,1 Toby J. Phesse,2 Harry Begthel,1 Elena Sancho,3 Alicia M. Cole,5 Alex Gregorieff,1 Ignacio Moreno de Alboran,4 Hans Clevers,1* and Alan R. Clarke2

Hubrecht Laboratory, Nederlands Institute for Developmental Biology, Upsalalaan 8, 3584 CT Utrecht, The Netherlands,1 Cardiff School of Biosciences, Cardiff University, Cardiff, United Kingdom CF10 3US,2 Biomedical Research Institute, Barcelona Science Park, Barcelona 08028, Spain,3 Department of Immunology and Oncology, Centro Nacional de Biotecnologia/CSIC, Cantoblanco, Madrid E-28049, Spain,4 The Beatson Institute, Garscube Estate, Glasgow, United Kingdom5

Received 9 May 2006/ Returned for modification 12 June 2006/ Accepted 12 August 2006

Inhibition of the mutationally activated Wnt cascade in colorectal cancer cell lines induces a rapid G1 arrest and subsequent differentiation. This arrest can be overcome by maintaining expression of a single Tcf4 target gene, the proto-oncogene c-Myc. Since colorectal cancer cells share many molecular characteristics with proliferative crypt progenitors, we have assessed the physiological role of c-Myc in adult crypts by conditional gene deletion. c-Myc-deficient crypts are lost within weeks and replaced by c-Myc-proficient crypts through a fission process of crypts that have escaped gene deletion. Although c-Myc–/– crypt cells remain in the cell cycle, they are on average much smaller than wild-type cells, cycle slower, and divide at a smaller cell size. c-Myc appears essential for crypt progenitor cells to provide the necessary biosynthetic capacity to successfully progress through the cell cycle.

* Corresponding author. Mailing address: Hubrecht Laboratory, Nederlands Institute for Developmental Biology, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands. Phone: (31) 30 212 1800. Fax: (31) 30 251 6464. E-mail: clevers{at}niob.knaw.nl.

{triangledown} Published ahead of print on 5 September 2006.

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

Molecular and Cellular Biology, November 2006, p. 8418-8426, Vol. 26, No. 22
0270-7306/06/$08.00+0     doi:10.1128/MCB.00821-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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