Information

Molecular mechanisms underlying neural development impairment in CdLS models


Cornelia de Lange Syndrome (CdLS) is a rare genetic disease, affecting multiple organs including the central nervous system (CNS). CdLS is mainly caused by dominant autosomal or X-linked mutations in five genes: NIPBL, SMC1A, SMC3, RAD21, and HDAC8. These genes encode for proteins of the cohesin complex, which plays a pivotal role in gene expression regulation. Indeed, we and others have previously reported that the canonical WNT pathway, a master controller of neurodevelopment, is downregulated in CdLS models.

Here, we explored possible ameliorative effects of chemical activation of WNT pathway in in vitro and in vivo CdLS models. First, we treated lymphoblastoid cell lines from healthy donors and CdLS patients with activators of the WNT pathway during the exponential phase of growth. We have found that lithium treatment restored proliferation rate and induced CyclinD1 gene expression, which are usually found reduced in cells of CdLS patients. We then analyzed an in vitro murine model of CdLS, in which neural stem cells proliferation and differentiation are significantly reduced. Such defects were rescued upon chemical exposure to lithium. Finally, we used a Drosophila melanogaster CdLS model which shows abnormal development of the mushroom body (MB), a CNS structure involved in learning and memory. Upon feeding on lithium, a significant rescue of MB morphology was observed across generations.

Together, our data confirm impairment of WNT canonical pathway in CdLS, possibly explaining the typical neurodevelopmental alterations, and reveal that WNT activators, such as lithium, could contribute to develop CdLS therapies in the future.

Conflicts of interest: none.

Weitere Seiten mit demselben Thema finden Autonomic nervous system7 Autonomic nervous system21

Presenting Author: Valentina Massa
Authors:Chiara Parodi 1, Paolo Grazioli 1, Daniele Bottai 1, Elisabetta Di Fede 1, Esi Taci 1, Raffaella Adami 1, Aida Zulueta 1, Cristina Gervasini 1, Thomas Vaccari 2, Angelo Selicorni 3, Valentina Massa 1


1 Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milano, 20142, Italia
2 Dipartimento di Bioscienze Università degli Studi di Milano, Milano, 20131, Italia
3 UOC Pediatria, ASST Lariana, Como, Italy.

Source:
Pagehistory
Zuletzt geändert von Gerritjan Koekkoek am 2024/08/25 10:38
Erstellt von Gerritjan Koekkoek am 2019/07/09 14:45

                                                                                                                                                                                                                                                                                                                                                                                                                                       

Thema zu diesem Thema
Senses
'
Information

  

Über den Inhalt der Website

Alle Informationen auf dieser WebSite dienen ausschließlich der Aufklärung. Der richtige Ort, um spezifischen medizinischen Rat, Diagnosen und Behandlungen zu erhalten, ist Ihr Arzt. Die Nutzung dieser Website erfolgt ausschließlich auf eigene Gefahr. Wenn Sie etwas finden, das Ihrer Meinung nach einer Korrektur oder Klärung bedarf, lassen Sie es uns bitte wissen: 

Senden Sie eine E-Mail: info@cdlsWorld.org