The Emerging Roles of<scp>LIS</scp>1 Biomechanics in Cellular and Cortical Homeostasis

Kshirsagarand, Aditya; Reiner, Orly

doi:10.1002/9781119860914.ch18

Cited by 1 publication

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“…Previous studies have indicated that brain regions have ECM content variability 65 . The observed proteomic changes in the corticOs partially correlated with corresponding transcriptomics data (mRNA and small-RNA), underscoring the roles of LIS1 in post-transcriptional regulation 16, 24, 41 . LIS1 is an RNA-binding protein involved in post-transcriptional regulation and governs the physical properties of embryonic stem cells 41 .…”

Section: Discussionsupporting

confidence: 53%

“…Lissencephaly, characterized by the absence of cortical convolutions, provides insights into human brain fold formation. LIS1 mutations, prevalent in lissencephaly patients, impact the scaffold protein LIS1, affecting cytoplasmic dynein, RNA interactions, splicing, and gene transcription [24][25][26] . Studying this disease in mouse models has been useful but limited since their cortex naturally lacks convolutions.…”

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confidence: 99%

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

Zur,

Bhattacharya,

Dror

et al. 2024

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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.

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