Functional and cell-specific regulation of the Brn-3b transcription factor by microRNAs.
Doctoral thesis, UCL (University College London).
Post-transcriptional gene regulation is a very powerful and evolutionary conserved mechanism which allows cells to finely modulate gene expression by acting at the level of their mRNAs. In this thesis the post-transcriptional regulation of the Brn-3b transcription factor was analyzed as a case study. This protein belongs to the POUIV family and to the homeobox super-family of transcription factors which are involved in neuronal differentiation and body patterning. The data presented in this thesis show that regulatory sequences contained in the 3’UTR of Brn-3b mediate the degradation of its mRNA in some neuronal cell lines. Furthermore, the regions regulating this effect have been characterized and two different microRNAs, very short RNA molecules which are key players in the post-transcriptional regulation of mRNAs, have been found to be directly involved in regulating the levels of Brn-3b. As Brn-3b plays an essential role in the survival of retinal ganglion cells, it was also investigated whether its mRNA is similarly regulated in a retinal ganglion cell line (RGC-5) as it occurs in other neuronal cell lines. Intriguingly, possibly due to its pro-survival role, Brn-3b is protected from degradation by microRNAs in RGC-5 cells in contrast to its fate in other cell types. Furthermore, one of the two microRNAs involved in its regulation is not expressed in the RGC-5 cell line, paralleling its expression profile in primary RGCs. Following a brief analysis concerning the possible regulation of Brn-3b in primary retinal ganglion cells, the possible general role of post transcriptional gene regulation was assessed by evaluating the role of Dicer in the differentiation of primary retinal ganglion cells. This showed that Dicer, one of the key enzymes in the production of microRNAs, might be involved in the modulation of neuronal differentiation markers and might thus have a direct role in retinal ganglion cell differentiation. Overall this thesis provides evidences that post-transcriptional gene regulation is a mechanism which might modulate the levels of mRNA molecules depending on whether the encoded protein has a pro-survival role. Furthermore, preliminary evidences suggest that Dicer, a key enzyme in the production of microRNAs, might have a role in the modulation of retinal ganglion cells differentiation markers.
|Title:||Functional and cell-specific regulation of the Brn-3b transcription factor by microRNAs|
|Open access status:||An open access version is available from UCL Discovery|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Child Health > Department of Genes, Development and Disease > ICH - Medical Molecular Biology Unit|
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