Lithium ameliorates Cornelia de Lange syndrome associated phenotypes in experimental models

ABSTRACTCornelia 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.

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Lithium as a possible therapeutic strategy for Cornelia de Lange syndrome

Cell Death Discovery ◽

10.1038/s41420-021-00414-2 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Paolo Grazioli ◽

Chiara Parodi ◽

Milena Mariani ◽

Daniele Bottai ◽

Elisabetta Di Fede ◽

...

Keyword(s):

Wnt Pathway ◽

Cellular Proliferation ◽

Chemical Activation ◽

Clinical Manifestations ◽

Experimental Models ◽

Proliferation Rate ◽

Cornelia De Lange Syndrome ◽

Canonical Wnt Pathway ◽

Cornelia De Lange ◽

Canonical Wnt

AbstractCornelia 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 the 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.

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Cornelia de Lange Syndrome: NIPBL haploinsufficiency downregulates canonical Wnt pathway in zebrafish embryos and patients fibroblasts

Cell Death and Disease ◽

10.1038/cddis.2013.371 ◽

2013 ◽

Vol 4 (10) ◽

pp. e866-e866 ◽

Cited By ~ 31

Author(s):

A Pistocchi ◽

G Fazio ◽

A Cereda ◽

L Ferrari ◽

L R Bettini ◽

...

Keyword(s):

Wnt Pathway ◽

Cornelia De Lange Syndrome ◽

Zebrafish Embryos ◽

Canonical Wnt Pathway ◽

Cornelia De Lange ◽

Canonical Wnt

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The effect of Wnt9A induced by lithium chloride on β-catenin and colorectal cancer cell proliferation.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.4_suppl.631 ◽

2016 ◽

Vol 34 (4_suppl) ◽

pp. 631-631

Author(s):

Donald Peter Braun ◽

Irshad Ali

Keyword(s):

Cell Proliferation ◽

Wnt Pathway ◽

Cellular Proliferation ◽

Cancer Cell Proliferation ◽

Protein Levels ◽

Canonical Wnt Pathway ◽

Proliferation And Apoptosis ◽

Canonical Wnt ◽

Total P ◽

Direct Induction

631 Background: Malignant tissues are characterized by uncontrolled proliferation and dysfunctional differentiation which often results from dysregulated Wnt signaling. β-catenin, a second messenger upregulated in neoplastic tissues is utilized by the canonical Wnt pathway (CWP) to promote cellular proliferation. In healthy tissues CWP is stringently controlled by components of the non-canonical Wnt pathway (NCWP). The NCWP, which does not utilize β-catenin for its activity, acts in concert with the CWP to maintain homeostasis in healthy tissues. Our recent studies in CRC cells indicate that LiCl increases expression of the NCWP ligand, Wnt9A leading to activation of the NCWP. Suppressing Wnt9A significantly attenuates LiCl-mediated inhibition of CRC cell proliferation. The present study investigated the capacity of Wnt9A to directly modulate expression of β-catenin mRNA and/or protein levels in CRC cells, and the effects on proliferation and apoptosis. Methods: Primary CRC lines established from resected tumors of 5 patients with metastatic disease were treated with LiCl and Wnt9A protein. Cellular proliferation and apoptosis were determined by MTS and caspase 3 assays. Total and activated β-catenin protein were determined by ELISA and Wnt pathway genes and β-catenin mRNA were determined with PCR arrays. Results: LiCl inhibited CRC proliferation (p<0.001) and increased apoptosis (p<0.01) which coincided with a 23-fold (p<0.025) increase of the NCWP ligand Wnt9A. LiCl decreased β-catenin mRNA (p<0.03) and suppressed protein levels of the total (p<0.025) and the activated form of β-catenin. Recombinant Wnt9A protein emulated LiCl effects by inhibiting proliferation (p<0.001), increasing apoptosis (p<0.03) and suppressing activated β-catenin protein (p<0.001) in CRC cells. Conclusions: This study demonstrates a novel mechanism for inhibiting CRC cell proliferation through suppression of activated β-catenin levels by the non-canonical Wnt ligand, Wnt9A. These results suggest that in CRC tumors that are driven by β-catenin, activation of the non-canonical pathway and/or direct induction of or treatment with Wnt9A protein may be therapeutically beneficial.

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