Ciliated-cell differentiation and gene expression

Ciliated cells play an integral role in the defense mechanisms of the respi ratory system. By the coordinated beating of their cilia they provide the f orce necessary to clear potentially harmful material from the airways. We h ave been investigating the regulation of ciliated-cell differentiation and gene expression. Using a culture system that allows us to positively or neg atively regulate the development of the ciliated-cell phenotype, we have pr eviously reported that the expression of axonemal dynein heavy chain mRNAs are regulated in parallel with the development of ciliated cells. To identi fy other genes important to the development or function of ciliated cells, differential display was used to compare mRNA isolated from cultures of cil iated or nonciliated rat tracheal epithelial cells. Two novel genes, KPL1 a nd KPL2, have been identified whose expression is increased in parallel wit h ciliated-cell differentiation. Two transcripts of KPL1 are expressed in a tissue-specific pattern; KPL1 is particularly highly expressed in brain. T he sequence of KPL1 predicts a 188 or 223 amino acid protein which contains a pleckstrin homology domain. Pleckstrin homology domains have been shown to bind inositolphosphates and G-proteins and function as signal-dependent membrane adapters. KPL1 therefore may function in a signal transduction pat hway important to the development or maintenance of the ciliated-cell pheno type. KPL2 shows more limited distribution and is predominantly expressed i n tissues which contain axonemes. KPL2 is predicted to encode a 1744 amino acid protein which contains many functional motifs, including nuclear local ization signals, an ATP-binding domain, a proline-rich region, and a calpon in homology domain. KPL2 may thus be involved in transmitting signals to th e nucleus during ciliated-cell differentiation.