The transcriptional repressor CDP (Cutl1) is essential for epithelial celldifferentiation of the lung and the hair follicle

The mammalian Cutl1 gene codes for the CCAAT displacement protein (CDP), wh ich has been implicated as a transcriptional repressor in diverse processes such as terminal differentiation, cell cycle progression, and the control of nuclear matrix attachment regions. To investigate the in vivo function o f Cutl1, we have replaced the C-terminal Cut repeat 3 and homeodomain exons with an in-frame lacZ gene by targeted mutagenesis in the mouse. The CDP-l acZ fusion protein is retained in the cytoplasm and fails to repress gene t ranscription, indicating that the Cutl1(lacZ) allele corresponds to a null mutation. Cutl1 mutant mice on inbred genetic backgrounds are born at Mende lian frequency, but die shortly after birth because of retarded differentia tion of the lung epithelia, which indicates an essential role of CDP in lun g maturation. A less pronounced delay in lung development allows Cutl1 muta nt mice on an outbred background to survive beyond birth. These mice are gr owth-retarded and develop an abnormal pelage because of disrupted hair foll icle morphogenesis. The inner root sheath (IRS) is reduced, and the transcr iption of Sonic hedgehog and IRS-specific genes is deregulated in Cutl1 mut ant hair follicles, consistent with the specific expression of Cutl1 in the progenitors and cell lineages of the IRS. These data implicate CDP in cell -lineage specification during hair follicle morphogenesis, which resembles the role of the related Cut protein in specifying cell fates during Drosoph ila development.