Cornelia de Lange syndrome (CdLS) is a rare genetic disorder affecting neurodevelopment and the gastrointestinal and musculoskeletal systems. CdLS is caused by mutations within NIPBL, SMC1A, SMC3, RAD21, HDAC8 and BRD4 genes. These genes codify for the cohesin complex (or associated proteins), a multiprotein structure playing a role in chromatid adhesion, DNA repair and gene expression regulation. Our laboratory has shown that a strong correlation exists between cohesin complex function and WNT signalling, an intracellular pathway involved in regulation of expression of several genes controlling cell division and embryonic development. Recently, it has been observed that in nipblb- and smc1a-loss-of-function zebrafish embryos, in NIPBL- and SMC1A- mutated patient fibroblasts and in CdLS murine neural stem cells (NSCs) similar patterns of canonical WNT pathway alterations and cyclinD1 downregulation are present. Indeed, zebrafish embryos adverse phenotype was rescued by chemical activation of the WNT pathway. Drosophila melanogaster is an inexpensive model to study CdLS and to screen in vivo for therapeutic compounds. Therefore, we have used flies’ strains mutated in nipped-B and hdac3 genes (respectively NIPBL and HDAC8 in humans) for assessing the existing correlation between cohesin complex and WNT pathway. Moreover, we have selected D. melanogaster mutants to screen for chemicals that revert the CdLS associated-phenotypes efficiently. In particular, we have tested WNT activators in order to investigate which effects they have on the mutated flies, assessing body weight and changes in brain structures (i.e. mushroom bodies) and possibly select compounds to test on vertebrate models. Funding: This work has been supported by Fondazione Cariplo, grant 2015-0783 to Valentina Massa.

Modulating the WNT pathway in Drosophila models of Cornelia de Lange Syndrome / P. Grazioli, T. Vaccari, V. Massa. ((Intervento presentato al 77. convegno Society for Developmental Biology tenutosi a Portland nel 2018.

Modulating the WNT pathway in Drosophila models of Cornelia de Lange Syndrome

P. Grazioli;T. Vaccari;V. Massa
2018-07-21

Abstract

Cornelia de Lange syndrome (CdLS) is a rare genetic disorder affecting neurodevelopment and the gastrointestinal and musculoskeletal systems. CdLS is caused by mutations within NIPBL, SMC1A, SMC3, RAD21, HDAC8 and BRD4 genes. These genes codify for the cohesin complex (or associated proteins), a multiprotein structure playing a role in chromatid adhesion, DNA repair and gene expression regulation. Our laboratory has shown that a strong correlation exists between cohesin complex function and WNT signalling, an intracellular pathway involved in regulation of expression of several genes controlling cell division and embryonic development. Recently, it has been observed that in nipblb- and smc1a-loss-of-function zebrafish embryos, in NIPBL- and SMC1A- mutated patient fibroblasts and in CdLS murine neural stem cells (NSCs) similar patterns of canonical WNT pathway alterations and cyclinD1 downregulation are present. Indeed, zebrafish embryos adverse phenotype was rescued by chemical activation of the WNT pathway. Drosophila melanogaster is an inexpensive model to study CdLS and to screen in vivo for therapeutic compounds. Therefore, we have used flies’ strains mutated in nipped-B and hdac3 genes (respectively NIPBL and HDAC8 in humans) for assessing the existing correlation between cohesin complex and WNT pathway. Moreover, we have selected D. melanogaster mutants to screen for chemicals that revert the CdLS associated-phenotypes efficiently. In particular, we have tested WNT activators in order to investigate which effects they have on the mutated flies, assessing body weight and changes in brain structures (i.e. mushroom bodies) and possibly select compounds to test on vertebrate models. Funding: This work has been supported by Fondazione Cariplo, grant 2015-0783 to Valentina Massa.
Cornelia de Lange Syndrome; canonical WNT pathway; Drosophila melanogaster
Settore BIO/13 - Biologia Applicata
Modulating the WNT pathway in Drosophila models of Cornelia de Lange Syndrome / P. Grazioli, T. Vaccari, V. Massa. ((Intervento presentato al 77. convegno Society for Developmental Biology tenutosi a Portland nel 2018.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/625344
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