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Analysis of the molecular interactions between Msx1 and other key players during mouse limb development

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Resumo:In vertebrates, the anteroposterior (AP) growth and patterning of the limb bud rely on an intricate regulatory genetic network involving Shh and Gli3. Although the mechanism allowing Shh to modulate Gli3 activity is well documented, the role of Msx genes, which constitute a small family of genes encoding homeodomain transcription factors that have been implicated in AP limb patterning, within this genetic network remains poorly understood. Based on empirical evidence generated by previous studies, we hypothesized that Msx genes may interact with the transcription factor Gli3, particularly, with its repressor form, Gli3R in order to drive limb morphogenesis. To test this hypothesis, we performed a series of protein interaction assays using the Proximity Ligation Assay (PLA) technique followed by quantification analysis. Using this technique we were able to produce evidence supporting our initial assumption admitting the in vivo interaction between the transcription factors Msx1 and Gli3R in the forelimb and hindlimb bud at 11.5 dpc. In parallel, we also investigated the involvement of these transcription factors in the BMP signaling pathway, by testing their ability to interact with the PSmad1,5,8 protein complex, the intracellular transducer of the BMP signaling cascade. Using the same experimental approach, we were able to demonstrate that both Msx1 and Gli3R interact with this protein complex in mesenchymal cells of the forelimb at 11.5 dpc. Based on these results and on the fact that the BMP signaling pathway has been systematically implicated in the apoptotic events taking place in the limb, together with the observation that the absence of Msx genes and/or Gli3 result in phenotypes concomitant with apoptosis impairment, we propose that Msx1, Gli3R and the Psmad1,5,8 proteins interact with each other in order to form a trimeric nuclear transcriptional complex that will drive the expression of BMP target genes involved in cell death regulation.
Autores principais:Carvalho, Joana Cristina Reino, 1990-
Assunto:Biologia do desenvolvimento Transcrição genética Apoptose Teses de mestrado - 2013
Ano:2013
País:Portugal
Tipo de documento:dissertação de mestrado
Tipo de acesso:acesso aberto
Instituição associada:Universidade de Lisboa
Idioma:inglês
Origem:Repositório da Universidade de Lisboa

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