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Regulation of the Drosophila lin-41 homologue dappled by let-7 reveals conservation of a regulatory mechanism within the LIN-41 subclade
Södertörns högskola, Institutionen för livsvetenskaper. Karolinska Institute.
Stockholms universitet.
Stockholms universitet.
Södertörns högskola, Institutionen för livsvetenskaper.
2008 (Engelska)Ingår i: Developmental Dynamics, ISSN 1058-8388, E-ISSN 1097-0177, Vol. 237, nr 1, s. 196-208Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Drosophila Dappled (DPLD) is a member of the RBCC/TRIM superfamily, a protein family involved in numerous diverse processes such as developmental timing and asymmetric cell divisions. DPLD belongs to the LIN-41 subclade, several members of which are micro RNA (miRNA) regulated. We re-examined the LIN-41 subclade members and their relation to other RBCC/TRIMs and dpld paralogs, and identified a new Drosophila muscle specific RBCC/TRIM: Another B-Box Affiliate, ABBA. In silico predictions of candidate miRNA regulators of dpld identified let-7 as the strongest candidate. Overexpression of dpld led to abnormal eye development, indicating that strict regulation of dpld mRNA levels is crucial for normal eye development. This phenotype was sensitive to let-7 dosage, suggesting let-7 regulation of dpld in the eye disc. A cell-based assay verified let-7 miRNA down-regulation of dpld expression by means of its 3'-untranslated region. Thus, dpld seems also to be miRNA regulated, suggesting that miRNAs represent an ancient mechanism of LIN-41 regulation.

Ort, förlag, år, upplaga, sidor
2008. Vol. 237, nr 1, s. 196-208
Nationell ämneskategori
Biologiska vetenskaper
Identifikatorer
URN: urn:nbn:se:sh:diva-14180DOI: 10.1002/dvdy.21396ISI: 000252386300019PubMedID: 18069688Scopus ID: 2-s2.0-38149087481OAI: oai:DiVA.org:sh-14180DiVA, id: diva2:466971
Tillgänglig från: 2011-12-18 Skapad: 2011-12-16 Senast uppdaterad: 2017-12-08Bibliografiskt granskad
Ingår i avhandling
1. A screen for mutations affecting PNS development in Drosophila identifies the trim gene, dappled
Öppna denna publikation i ny flik eller fönster >>A screen for mutations affecting PNS development in Drosophila identifies the trim gene, dappled
2008 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

The peripheral nervous system of Drosophila melanogaster contains a variety of sense organs, ranging from the relatively simple four celled bristle organ to the more complex compound eye. The development of each organ type is well described, providing a useful backdrop for functional studies of genes acting in one or more of the many processes involved in organogenesis. We have used the bristle organ to screen for genes affecting PNS development. Two of the candidates recovered via this approach, string (stg, Drosophila cdc25, the universal regulator of the G2 to M phase mitotic transition), and dappled (dpld, a poorly described gene implicated in tumor suppression) were selected for further study. Examination of stg mis-expression phenotypes in the adult bristle organ revealed cell fate transformations corresponding to the generation of two pIIa structural precursor cells at the expense of a neural precursor cell. This transformation most reasonably resulted from an abnormally short G2 arrest, indicating that the time spent in the G2 phase is crucial to correct cell fate determination. dpld is a member of the Tripartite Motif (TRIM) superfamily, members of which are involved in diverse biological processes e.g. proliferation, apoptosis and immune response. dpld belongs to a subgroup of NHL domain containing TRIM proteins, that are known to be involved in tumor suppression. Phylogenetic analysis placed dpld in the lin-41 sub-clade of the TRIM superfamily. A combination of insilico, genetic and cell culture assay approaches showed dpld to be susceptible to miRNA regulation. As homologous genes are also miRNA regulated this regulatory mechanism may be conserved throughout this sub-clade, between vertebrates and invertebrates. Pre-existing loss of function dpld alleles were characterized, however, subsequent complementation studies revealed that characteristic aspects of the described dpld phenotype, in fact mapped outside the dpld locus, and were caused by mutations of nearby genes. The tumor-causing locus was mapped to the Cytb5 gene (mutated in both pre-existing dpld alleles), while the embryonic lethality and PNS phenotype was mapped to the scraps locus. scraps encodes for Drosophila Anillin, known to be required during cytokinesis. We provide the first characterization of scraps null alleles and detail a biased requirement for scraps within neural precursor cells of the embryonic PNS. A novel loss of function dpld allele was recovered. This mutation is lethal, however it does not have an associated tumor phenotype. This finding, together with our complementation study indicates that the existing classification of dpld as a tumor suppressor is inaccurate. Subsequent studies detail dpld requirements in the developing fly retina. There, dpld mutation resulted in excessive proliferation, while conversely, mis-expression caused a reduction. Additionally, and perhaps consequently, cell differentiation was affected. Thus, regulation of proliferation by NHL-TRIM genes seems a conserved feature. We additionally identified a novel Drosophila TRIM gene of the same class as dpld, which we have dubbed another bbox affiliate (abba), bringing the number of NHL containing TRIM genes in Drosophila to four.

Ort, förlag, år, upplaga, sidor
Stockholm: Karolinska institutet, 2008. s. 68
Nationell ämneskategori
Biologiska vetenskaper
Identifikatorer
urn:nbn:se:sh:diva-31553 (URN)978-91-7357-589-8 (ISBN)
Disputation
2008-05-30, MB416, Moas Båge, Huddinge, 13:00
Opponent
Handledare
Tillgänglig från: 2016-12-29 Skapad: 2016-12-29 Senast uppdaterad: 2016-12-29Bibliografiskt granskad

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O'Farrell, FergalKylsten, Per

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