The molecular diversity of many gene products functioning in the nervous system is enhanced by alternative splicing and adenosine-toinosine editing of pre-mRNA. Using RDL, a Drosophila melanogaster GABA-gated ion channel, we examined the functional impact of RNA editing at several sites along with alternative splicing of more than one exon. We show that alternative splicing and RNA editing have a combined influence on the potency of the neurotransmitter GABA, and the editing isoforms detected in vivo span the entire functional range of potencies seen for all possible edit variants expressed in Xenopus laevis oocytes. The extent of RNA editing is developmentally regulated and can also be linked to the choice of alternative exons. These results provide insights into how the rich diversity of signaling necessary for complex brain function can be achieved by relatively few genes.

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SummaryB-catenin is the central effector molecule of the canonical Wnt signalling pathway, which controls self-renewal of haematopoietic stem cells. Deregulation of this pathway occurs in various malignancies including myeloid leukaemias. The present study examined the functional outcome of stable b-catenin down-regulation through lentivirus-mediated expression of short hairpin RNA (shRNA). Reduction of the b-catenin levels in acute myeloid leukaemia (AML) cell lines and patient samples decelerated their in vitro proliferation ability without affecting cell viability. Transplantation of leukaemic cells with control or reduced levels of b-catenin in non-obese diabetic severe combined immunodeficient animals indicated that, while the immediate homing of the cells was unaffected, the bone marrow engraftment was directly dependent on b-catenin levels. Subsequent examination of bone sections revealed that b-catenin was implicated in the localization of AML to the endosteum. Examination of adhesion molecule expression before and after transplantation, revealed down-regulation of CD44 expression, accompanied by reduced in vitro adhesion. Gene expression analysis disclosed the presence of an autocrine compensatory mechanism, which responds to the reduced b-catenin levels by altering the expression of positive and negative pathway regulators. In conclusion, our study showed that b-catenin comprises an integral part of AML cell proliferation, cell cycle progression, and adhesion, and influences disease establishment in vivo.

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