Gene Expression Profiling in Cells with Enhanced ?-Secretase Activity

Magold, Alexandra I.; Cacquevel, Matthias; Fraering, Patrick C.

TERA and the anti-mitotic exit network antagonist 1 (AMN1) map to chromosome 12p11, which is interesting when considering the fact that chromosome 12 has been discussed to contain an unknown LOAD locus for over a decade, and in a recent study including 492 LOAD cases [57] [58] [59] . In our study, AMN1 transcription is decreased by 978-fold with enhanced c-secretase activity. The function of AMN1 is not known. However, several expression pattern based studies suggest it functions as a cilia gene in sensory neurons [60] . Another typical cilia gene is intraflagellar transport protein 81 (IFT81) which, among a dozen of known cilia genes, was also shown by the microarray to be differentially expressed with altered c-secretase activity (see also Fig. 3 ). More and more evidence has been emerging over the last years that primary cilia, in parallel to their well-established functions in sight, smell and mechanosensation, are key participants in intercellular signaling [61] . The importance of monocilia for the regeneration of olfactory neurons has only been better understood recently [62] . Subventricular zone (SVZ) astrocytes, providing glia as well as neurons for the mammalian olfactory bulb, have primary cilia [63] . They give rise to type C cells, which in turn generate neuroblasts [64] that migrate in the adult brain from the SVZ to the olfactory bulb along the cerebrospinal fluid (CSF) flow. The CSF flow depends on the beating of the ependymal cilia [65] . Cilia genes are not only relevant to the maintenance of adult regeneration in the brain since they uphold the constant flow of the CSF, but also because they are directly implicated in cell cycle control. Polycystins, for example, control the cell cycle through three major pathways with one depending directly on b-catenin [66] . A study of inversin has further shown that flow shear stress as sensed through cilia may regulate the Wnt signaling pathway through b-catenin [67, 68] . Given that fluid flow is crucial for the transport of neuroblasts in the SVZ, one could expect that bcatenin and the Wnt signaling pathway that connects our candidates are also functionally relevant to the cilia genes found in this study. We found both genes of unknown function TERA and AMN1 to be decreased in transcription with enhanced csecretase activity. TERA and AMN1 can be connected to neural stem cells through several types of cancer, neural differentiation (in the case of TERA) and through the role of monocilia for neurogenesis (in the case of AMN1). All in all, we have demonstrated that AMN1 and TERA are genes of basically unknown function that are worthy of further investigation to understand their roles in neurogenesis, cancer and c-secretase biology.