LIS1 RNA-binding orchestrates the mechanosensitive properties of embryonic stem cells in AGO2-dependent and independent ways

Kshirsagar, Aditya; Doroshev, Svetlana Maslov; Gorelik, Anna; Olender, Tsviya; Sapir, Tamar; Tsuboi, Daisuke; Rosenhek-Goldian, Irit; Malitsky, Sergey; Itkin, Maxim; Argoetti, Amir; Mandel-Gutfreund, Yael; Cohen, Sidney R.; Hanna, Jacob H.; Ulitsky, Igor; Kaibuchi, Kozo; Reiner, Orly

doi:10.1038/s41467-023-38797-8

Cited by 2 publications

(1 citation statement)

References 141 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Network analysis of this module identified three major clusters (Figure 2H). Notably, the first subset of proteins includes such involved in RNA splicing that have been previously identified as nuclear interactors of LIS1 in AGO2 gene knockout embryonic stem cells (36). Among them, NCL and DXCX3 have also been associated with pre-rRNA transcription, ribosome assembly, and translation of components of the core translational machinery (37, 38).…”

Section: Resultsmentioning

confidence: 99%

Unraveling LIS1-Lissencephaly: Insights from Cerebral Organoids Suggest Severity- Dependent Genotype-Phenotype Correlations, Molecular Mechanisms and Therapeutic Strategies

Rossetti

Fechtner

Maillard

et al. 2022

Preprint

View full text Add to dashboard Cite

Lissencephaly is a developmental cortical malformation characterized by reduced to absent gyri and a disorganized cortex. Heterozygous mutations in the LIS1 gene, encoding a regulator of the microtubule-motor dynein, were identified to cause lissencephaly with different severities. While the clinical disease spectrum correlates with the degree of lissencephaly, location and type of mutation does not. Here we present forebrain-type organoids from LIS1 patients with mild, moderate or severe lissencephaly that reflect disease severity in the degree of alterations of cytoarchitecture and neurogenesis. ScRNAseq data point toward a severity related dysregulation of progenitor cell homeostasis. Furthermore, we show that severity dependent alteration in microtubule stabilization is critical for the development of the phenotype. In addition, we found alterations in niche-dependent WNT-signaling mainly in severe patient-derived organoids. Thus, our data identify for the first time a clear association between the clinical severity grade of the patients and the molecular phenotype in the organoid model, suggest linked disease-mechanisms and show the sensitivity of organoid-based systems to capture different disease severities in vitro.

show abstract

Section: Resultsmentioning

confidence: 99%

Unraveling LIS1-Lissencephaly: Insights from Cerebral Organoids Suggest Severity- Dependent Genotype-Phenotype Correlations, Molecular Mechanisms and Therapeutic Strategies

Rossetti

Fechtner

Maillard

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

Altered Extracellular Matrix Structure and Elevated Stiffness in a Brain Organoid Model for Disease

Zur,

Bhattacharya,

Dror

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

The viscoelasticity of tissues impacts their shape, as well as the growth and differentiation of their cells. Nevertheless, little is known about changes in viscoelastic properties during brain malformations. Lissencephaly is a severe malformation of cortical development caused by LIS1 mutations, which results in a lack of cortical convolutions. Here, we show that human-derived brain organoids withLIS1mutation are stiffer than control ones at multiple developmental times. This stiffening is accompanied by abnormal ECM expression and organization, as well as elevated water content, as measured by diffusion-weighted MRI. Proteolytic cleavage of ECM components by short-term treatment with the catalytic subunit of MMP9 reduced the stiffening and water diffusion levels of mutated organoids to control levels. Finally, based on the molecular and rheological properties obtained, we generated a computational microstructure mechanical model that can successfully predict mechanical changes that follow differential ECM localization and integrity in the developing brain. Overall, our study reveals that LIS1 is essential for the expression and organization of ECM proteins during brain development, and its mutation leads to a substantial viscoelastic change. To our knowledge, this is the first study to elucidate how tissue mechanics change in disease states using human brain organoids.

show abstract

LIS1 RNA-binding orchestrates the mechanosensitive properties of embryonic stem cells in AGO2-dependent and independent ways

Cited by 2 publications

References 141 publications

Unraveling LIS1-Lissencephaly: Insights from Cerebral Organoids Suggest Severity- Dependent Genotype-Phenotype Correlations, Molecular Mechanisms and Therapeutic Strategies

Unraveling LIS1-Lissencephaly: Insights from Cerebral Organoids Suggest Severity- Dependent Genotype-Phenotype Correlations, Molecular Mechanisms and Therapeutic Strategies

Altered Extracellular Matrix Structure and Elevated Stiffness in a Brain Organoid Model for Disease

Contact Info

Product

Resources

About