MicroRNAs and Tissue Development
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AbstractExpression of microRNA (miRNA) in developing murine tissues was studied: focus being on the miR-17-92 cluster (oncomir-1) and two paralogous clusters, miR-106a-363 and miR-106b-25. Using microarrays we mapped the miRNA expression profile at selected times during development of two oral tissues: tooth germ and submandibular salivary gland. MiRNA expression in developing liver was also monitored. MiRNA expression was found to be highly abundant during development of these tissues: five of the miRNAs encoded in the miR-17-92 cluster exhibited decreased expression at postnatal stages compared to embryonic stages (Paper I).
Despite the oncogenic role of the miR-17-92 cluster, the function of the cluster in normal tissue remains unclear. However, studies have implicated the miR-17-92 cluster in development, and the cluster may be involved in regulation of cell cycle. The miR-106b-25 cluster has been associated with analogous functions.
Expression of the miR-17-92 primary transcript and all miRNAs encoded in this cluster was measured in nine different murine tissues at various developmental stages using real-time PCR. The relative levels of expression all miRNAs encoded in the miR-17-92 cluster exhibited decreased expression during development. Moreover, the pattern of expression of the primary transcript correlated to that of the mature miRNAs, although, the level of expression of the individual miRNAs were markedly different. These observations indicate that the level of expression of miRNAs encoded in the miR-17-92 cluster is regulated at a post-transcriptional level. To investigate possible involvement of members of the miR-17-92 cluster in proliferation the levels of expression of all members of the cluster were monitored at selected cell passages of cultured primary oral keratinocytes. The results indicate miRNAs of the miR-17-92 cluster may promote cell proliferation and inhibit differentiation (Paper II).
Possible functions of the members of the miR-106a-363 cluster, often considered as non-functional, was investigated by transfecting cells with miR-363* mimic. Transfection with miR-363* mimic led to decreased cellular proliferation and to decreased levels of expression of all miRNAs encoded by the miR-17-92 and miR-106b-25 clusters, suggesting that miR-363* may exert an inhibitory effect on expression of miRNAs derived from paralogous clusters. Therefore, the results suggest that the miRNAs*-species are not always by-products devoid of biological function (Paper III).
List of papers. Papers 1-3 are removed from the thesis due to copyright restrictions.
Paper 1: Jevnaker, A.M., and H. Osmundsen. 2008. MicroRNA expression profiling of the developing murine molar tooth germ and the developing murine submandibular salivary gland. Arch Oral Biol. 53:629-645. doi:10.1016/j.archoralbio.2008.01.014
Paper 2: Jevnaker, A.M., Khuu, C., Kjøle, E., Bryne, M. and H. Osmundsen. 2010. Expression of members of the miRNA17-92 cluster during development and in carcinogenesis. Journal of Cellulare Physiology. 226: 2257-2266. doi:10.1002/jcp.22562
Paper 3: Khuu, C., Jevnaker, A.M., Bryne, M. and H. Osmundsen. 2011. Regulation of expression of microRNAs encoded by paralogous, polycistronic, clusters. A possible role for miR-363*. Submitted to Journal of Cellular Physiology.