The mammalian Cutl1 gene codes for the CCAAT displacement protein (CDP), which 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 of 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-lacZ fusion protein is retained in the cytoplasm and fails to repress gene transcription, indicating that the Cutl1(lacZ) allele corresponds to a null mutation. Cutl1 mutant mice on inbred genetic backgrounds are born at Mendelian frequency, but die shortly after birth because of retarded differentiation of the lung epithelia, which indicates an essential role of CDP in lung maturation. A less pronounced delay in lung development allows Cutl1 mutant mice on an outbred background to survive beyond birth. These mice are growth-retarded and develop an abnormal pelage because of disrupted hair follicle morphogenesis. The inner root sheath (IRS) is reduced, and the transcription of Sonic hedgehog and IRS-specific genes is deregulated in Cutl1 mutant 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 Drosophila development.

中文翻译：

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转录抑制因子CDP（Cutl1）对于肺和毛囊的上皮细胞分化至关重要。

哺乳动物的Cutl1基因编码CCAAT置换蛋白（CDP），已被认为是转录阻遏物，涉及多种过程，例如终末分化，细胞周期进程以及对核基质附着区域的控制。为了研究Cutl1的体内功能，我们已经通过在小鼠中进行靶向诱变，将C端Cut重复序列3和同源域外显子替换为框架内lacZ基因。CDP-lacZ融合蛋白保留在细胞质中，无法抑制基因转录，表明Cutl1（lacZ）等位基因对应于无效突变。具有近交遗传背景的Cutl1突变小鼠以孟德尔频率出生，但由于肺上皮细胞分化迟缓而在出生后不久死亡，这表明CDP在肺成熟中起着至关重要的作用。肺发育的延迟较不明显，可使近交背景下的Cutl1突变小鼠存活至出生后。这些小鼠由于毛囊形态发生的破坏而发育迟缓，并形成异常的皮疹。内根鞘（IRS）减少，并且在Cutl1突变型毛囊中Sonic刺猬和IRS特异性基因的转录被下调，这与Cutl1在IRS的祖细胞和细胞谱系中的特异性表达相一致。这些数据将CDP包含在毛囊形态发生过程中的细胞谱系规范中，类似于果蝇发育过程中相关Cut蛋白在确定细胞命运中的作用。这些小鼠由于毛囊形态发生的破坏而发育迟缓，并形成异常的皮疹。内根鞘（IRS）减少，并且在Cutl1突变型毛囊中Sonic刺猬和IRS特异性基因的转录被下调，这与Cutl1在IRS的祖细胞和细胞谱系中的特异性表达相一致。这些数据将CDP包含在毛囊形态发生过程中的细胞谱系规范中，类似于果蝇发育过程中相关Cut蛋白在确定细胞命运中的作用。这些小鼠由于毛囊形态发生的破坏而发育迟缓，并发育异常的皮。内根鞘（IRS）减少，并且在Cutl1突变型毛囊中Sonic刺猬和IRS特异性基因的转录被下调，这与Cutl1在IRS的祖细胞和细胞谱系中的特异性表达相一致。这些数据将CDP包含在毛囊形态发生过程中的细胞谱系规范中，类似于果蝇发育过程中相关Cut蛋白在确定细胞命运中的作用。