title: Genetic ablation of the CDP/Cux protein C terminus results in hair cycle defects and reduced male fertility.
abstract: 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 (Cutl1(tm2Ejn), 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 Cutl1(tm2Ejn/tm2Ejn) mice suggest that CDP/Cux is required for the developmental control of dermal and reproductive functions.
authors.affiliation: Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts 01655-0106, USA.
authors.forename: Mai X
authors.initials: MX
authors.lastname: Luong
authors.forename: Caroline M
authors.initials: CM
authors.lastname: van der Meijden
authors.forename: DongXia
authors.initials: D
authors.lastname: Xing
authors.forename: Ruth
authors.initials: R
authors.lastname: Hesselton
authors.forename: Edwin S
authors.initials: ES
authors.lastname: Monuki
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Jones
authors.forename: Jane B
authors.initials: JB
authors.lastname: Lian
authors.forename: Janet L
authors.initials: JL
authors.lastname: Stein
authors.forename: Gary S
authors.initials: GS
authors.lastname: Stein
authors.forename: Ellis J
authors.initials: EJ
authors.lastname: Neufeld
authors.forename: Andre J
authors.initials: AJ
authors.lastname: van Wijnen
mesh_terms: D000818:Animals; D001921:Brain / Q000196:embryology; D002451:Cell Compartmentation; D002467:Cell Nucleus; D004268:DNA-Binding Proteins / Q000378:metabolism; D020405:Dermis / Q000002:abnormalities; D004064:Digestive System / Q000196:embryology; D005317:Fetal Growth Retardation / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics*; D006720:Homozygote; D007039:Hypotrichosis / Q000235:genetics*; D007248:Infertility, Male / Q000235:genetics*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D016254:Mutagenesis, Insertional; D009687:Nuclear Proteins / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*
chemical_list: C000624101:Cux1 protein, mouse; D004268:DNA-Binding Proteins; C071109:HINF-D protein, human; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins