Related Experiment Video
Updated: Mar 30, 2026
Molecular Modulation by Lentivirus-Delivered Specific shRNAs in Endoplasmic Reticulum Stressed Neurons
Published on: April 24, 2021
Lithium ameliorates neural differentiation restoring cell death balance in Cornelia de Lange syndrome 2D and 3D
Chiara Parodi1, Antonella Lettieri1, Paolo Grazioli1
1Department of Health Sciences, Università degli Studi di Milano, Milan, Italy.
Abstract:
Cornelia de Lange syndrome (CdLS) is a rare genetic disorder that affects almost any organ, including the central nervous system. It leads to a wide range of neurodevelopmental delays, and there are currently no available clinical treatments. CdLS is caused by pathogenic variants in one of the 7 genes coding for the cohesin complex, a multimeric structure responsible for sister chromatid cohesion, or for cohesin ring-interacting proteins. Additionally, altered regulation of molecular pathways during development, including the canonical WNT pathway, can cause CdLS malformations. In our study, we evaluated the positive effects of using lithium as an activator of the canonical WNT pathway to ameliorate neural CdLS phenotype. We have exploited accurate two-dimensional (2D) and three-dimensional (3D) human central nervous system in vitro models representing disease-related neurobiological phenotypes: induced pluripotent stem cells of human origin (hiPSCs) differentiated into neural precursors, neurons, and brain organoids (BOs). CdLS models demonstrate alterations in proliferation and differentiation capabilities when mimicking HDAC8 haploinsufficiency. Furthermore, RNA-seq analysis of BOs revealed that both neuronal differentiation and the WNT pathway are downregulated when treated with the HDAC8 inhibitor alone. Following lithium treatment, cells show an enhanced ability to differentiate into the neuronal lineage. Additionally, our working hypothesis is that a specific mechanism may exist that, by connecting lipid metabolism, canonical WNT pathway, and cell death, results in typical CdLS neurodevelopmental deficits.
Insights
Cornelia de Lange syndrome (CdLS) neurodevelopmental deficits may be improved by lithium, which activates the WNT pathway. This study used human neural models to show lithium enhances neuronal differentiation in CdLS models.
Area of Science:
- Genetics
- Neuroscience
- Developmental Biology
Background:
- Cornelia de Lange syndrome (CdLS) is a rare genetic disorder impacting the central nervous system, causing neurodevelopmental delays with no current treatments.
- CdLS arises from genetic variants affecting the cohesin complex or its regulators, disrupting crucial developmental pathways like the WNT pathway.
- Understanding the molecular mechanisms underlying CdLS neurodevelopmental deficits is critical for therapeutic development.
Purpose of the Study:
- To investigate the potential of lithium, a WNT pathway activator, to ameliorate the neural phenotype in Cornelia de Lange syndrome (CdLS).
- To utilize advanced human in vitro models of the central nervous system to study CdLS-related neurobiological alterations.
Main Methods:
- Developed and utilized 2D and 3D human in vitro models, including induced pluripotent stem cells (hiPSCs) differentiated into neural precursors, neurons, and brain organoids (BOs).
- Mimicked HDAC8 haploinsufficiency in CdLS models to assess proliferation and differentiation defects.
- Employed RNA-sequencing (RNA-seq) analysis on brain organoids to evaluate gene expression changes and pathway alterations.
Main Results:
- CdLS models exhibited impaired neural proliferation and differentiation, particularly when mimicking HDAC8 haploinsufficiency.
- RNA-seq analysis revealed downregulation of neuronal differentiation and the WNT pathway in CdLS brain organoids treated with an HDAC8 inhibitor.
- Lithium treatment significantly enhanced neuronal differentiation in the CdLS models, suggesting a therapeutic benefit.
Conclusions:
- Lithium shows promise as a therapeutic agent for ameliorating the neural phenotype in CdLS by activating the WNT pathway.
- The study highlights the role of WNT pathway dysregulation and potential connections to lipid metabolism and cell death in CdLS neurodevelopmental deficits.
- Human in vitro neural models are effective tools for dissecting disease mechanisms and testing potential therapeutic interventions for rare genetic disorders like CdLS.
