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Molecular and Cellular Biology, March 2002, p. 1424-1437, Vol. 22, No. 5
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.5.1424-1437.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Genetic Ablation of the CDP/Cux Protein C Terminus Results in Hair Cycle Defects and Reduced Male Fertility

Mai X. Luong,1 Caroline M. van der Meijden,1 DongXia Xing,1 Ruth Hesselton,1 Edwin S. Monuki,2 Stephen N. Jones,1 Jane B. Lian,1 Janet L. Stein,1 Gary S. Stein,1 Ellis J. Neufeld,3 and Andre J. van Wijnen1*

Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts 01655-0106,1 Department of Neurology, Harvard Medical School, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine,2 Division of Hematology, Children's Hospital, Boston, Massachusetts 021153

Received 21 June 2001/ Returned for modification 9 August 2001/ Accepted 12 November 2001

Murine CDP/Cux, a homologue of the Drosophila Cut homeoprotein, modulates the promoter activity of cell cycle-related and cell-type-specific genes. CDP/Cux interacts with histone gene promoters as the DNA binding subunit of a large nuclear complex (HiNF-D). CDP/Cux is a ubiquitous protein containing four conserved DNA binding domains: three Cut repeats and a homeodomain. In this study, we analyzed genetically targeted mice (Cutl1tm2Ejn, referred to as {Delta}C) that express a mutant CDP/Cux protein with a deletion of the C terminus, including the homeodomain. In comparison to the wild-type protein, indirect immunofluorescence showed that the mutant protein exhibited significantly reduced nuclear localization. Consistent with these data, DNA binding activity of HiNF-D was lost in nuclear extracts derived from mouse embryonic fibroblasts (MEFs) or adult tissues of homozygous mutant ({Delta}C-/-) mice, indicating the functional loss of CDP/Cux protein in the nucleus. No significant difference in growth characteristics or total histone H4 mRNA levels was observed between wild-type and {Delta}C-/- MEFs in culture. However, specific histone genes (H4.1 and H1) containing CDP/Cux binding sites have reduced expression levels in homozygous mutant MEFs. Stringent control of growth and differentiation appears to be compromised in vivo. Homozygous mutant mice have stunted growth (20 to 50% weight reduction), a high postnatal death rate of 60 to 70%, sparse abnormal coat hair, and severely reduced fertility. The deregulated hair cycle and severely diminished fertility in Cutl1tm2Ejn/tm2Ejn mice suggest that CDP/Cux is required for the developmental control of dermal and reproductive functions.

* Corresponding author. Mailing address: Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, MA 01655-0106. Phone: (508) 856-5625. Fax: (508) 856-6800. E-mail: andre.vanwijnen{at}umassmed.edu.

Molecular and Cellular Biology, March 2002, p. 1424-1437, Vol. 22, No. 5
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.5.1424-1437.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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