RT Journal Article
SR Electronic
T1 Lithium ameliorates Cornelia de Lange syndrome associated phenotypes in experimental models
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.07.15.204628
DO 10.1101/2020.07.15.204628
A1 Paolo Grazioli
A1 Chiara Parodi
A1 Milena Mariani
A1 Daniele Bottai
A1 Elisabetta Di Fede
A1 Aida Zulueta
A1 Laura Avagliano
A1 Anna Cereda
A1 Romano Tenconi
A1 Jolanta Wierzba
A1 Raffaella Adami
A1 Maria Iascone
A1 Paola Francesca Ajmone
A1 Thomas Vaccari
A1 Cristina Gervasini
A1 Angelo Selicorni
A1 Valentina Massa
YR 2020
UL http://biorxiv.org/content/early/2020/07/15/2020.07.15.204628.abstract
AB Cornelia de Lange Syndrome (CdLS) is a rare developmental disorder affecting a multitude of organs including the central nervous system, inducing a variable neurodevelopmental delay. CdLS malformations derive from deregulation of developmental pathways, inclusive of the canonical WNT pathway.We have evaluated MRI anomalies and behavioral and neurological clinical manifestations in CdLS patients. Importantly, we observed in our cohort a significant association between behavioral disturbance and structural abnormalities in brain structures of hindbrain embryonic origin.Considering the cumulative evidence on the cohesin-WNT-hindbrain shaping cascade, we have explored possible ameliorative effects of chemical activation of the canonical WNT pathway with lithium chloride in different models: (I) Drosophila melanogaster CdLS model showing a significant rescue of mushroom bodies morphology in the adult flies; (II) mouse neural stem cells restoring physiological levels in proliferation rate and differentiation capabilities toward the neuronal lineage; (III) lymphoblastoid cell lines from CdLS patients and healthy donors restoring cellular proliferation rate and inducing the expression of CyclinD1. This work supports a role for WNT-pathway regulation of CdLS brain and behavioral abnormalities and a consistent phenotype rescue by lithium in experimental models.Competing Interest StatementThe authors have declared no competing interest.