| Summary: | During the formation of the insect and mammalian nervous system the embryo activates specific programs of cellular differentiation along the main body axis so that the specification and organization of neural cells is set in coordination with axial level. At the genetic level such cellular specification programs rely on the regulated expression of a family of transcription factors encoded by the Hox genes. However, the precise molecular mechanisms controlling Hox expression in the nervous system are not well understood. In this thesis we investigate the molecular mechanisms underlying Hox gene expression within the Drosophila central nervous system (CNS) with a focus on post-transcriptional control via RNA binding proteins (RBP) and microRNAs (miRNAs). Much of the work is centred on the analysis of the Hox gene Ultrabithorax (Ubx) as this is the Hox gene for which post-transcriptional regulation is currently best understood. Through the combination of genetic, molecular and imaging methods we first show that the pan-neural RBP ELAV regulates Ubx RNA processing and protein expression during the embryonic development of the CNS. Secondly, using a suite of genetic and behavioural methods we report that Ubx repression by miRNAs encoded within the iab-4/iab-8 locus (miR-iab4/iab8) is required for the coordination of a specific larval behaviour: self-righting behaviour. Third, we explore the cellular basis of larval self-righting behaviour in the context of miRNA-dependent Ubx regulation and find that: (i) removal of miR-iab4/iab8 does not lead to major anatomical defects in the CNS or muscles; (ii) artificial increase in UBX protein expression in cholinergic interneurons disrupts self-righting behaviour; and (iii) UBX protein expression in cholinergic interneurons is regulated by miR-iab4/iab8. These observations imply that UBX regulation by miR-iab4/iab8 in cholinergic interneurons controls self-righting behaviour. Altogether our work adds to the current understanding of the molecular mechanisms underlying Hox gene expression during CNS formation and gives new insights on the role of RBP and miRNA regulation on the control of gene expression and behaviour.
|
|---|
