Loss of function of the DKC1 human gene causes the X-linked Dyskeratosis Congenital (X-DC) disease, whose main symptoms are abnormal skin pigmentation, nail dystrophy, mucosal leukoplakia, bone marrow failure and increased tumour susceptibility. DKC1 encodes a nucleolar protein, named dyskerin, whose sequence is characterized by a high degree of phylogenetic conservation. Eukaryal dyskerins represent one of the four proteic core components of the H/ACA small nucleolar RNA-associated ribonucleoprotein (snoRNP) complexes that are involved in rRNA processing, pseusourydilation of cellular RNAs, modulation of the efficiency of IRES-dependent translation, and stabilization of H/ACA snoRNAs. Besides participating in the formation of H/ACA snoRNPs, mammalian dyskerin also associates with telomeric RNA, which contains an H/ACA domain, being one of the essential components of the telomerase active complex.
One of the main challenges posed by X-DC pathogenesis is distinguishing between the effects caused by telomere shortening from those caused by altered snoRNPs functioning. Given that Drosophila lacks telomerase, and Drosophila dyskerin, encoded by the Nop60b/minifly (mfl) gene, is highly related to its human counterpart, this organism can serve as an useful model to investigate the telomerase-independent effects caused by depletion of snoRNP pseudouridine synthases.
In this thesis I evaluated the effects of in vivo localized mfl gene silencing on the development of the wing imaginal disc, which represents an excellent model to study the morphogenetic regulation of organ growth and patterning. I found that mfl silencing triggers a process of “apoptosis-induced proliferation” that is typical of regenerative phenomena. This process correlates with epithelial reorganization, that is marked by cytoskeletal remodeling, activation of the JNK pathway activity and transition of patches of cells from the epithelial to the mesenchimal state. Moreover, I observed that mfl silencing causes dysregulation of Notch signaling at the D/V boundary of the wing disc; this dysregulation cannot be attributed to apoptosis or to defective IRES- dependent translation of the Notch antagonist Hairless protein.
Altogheter, the results obtained reveal for the first time a close link that connects eukaryotic dyskerins with Notch signaling and JNK pathway. On the basis of their evolutionary conservation, I speculate that these events could be r!esponsible for at least some of the symptoms shown by X-DC patients
