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

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

doi:10.1038/s41467-023-38797-8

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

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

Lissencephaly-1 (LIS1) is associated with neurodevelopmental diseases and is known to regulate the molecular motor cytoplasmic dynein activity. Here we show that LIS1 is essential for the viability of mouse embryonic stem cells (mESCs), and it governs the physical properties of these cells. LIS1 dosage substantially affects gene expression, and we uncovered an unexpected interaction of LIS1 with RNA and RNA-binding proteins, most prominently the Argonaute complex. We demonstrate that LIS1 overexpression partially rescued the extracellular matrix (ECM) expression and mechanosensitive genes conferring stiffness to Argonaute null mESCs. Collectively, our data transforms the current perspective on the roles of LIS1 in post-transcriptional regulation underlying development and mechanosensitive processes.

Original language	English
Article number	3293
Number of pages	21
Journal	Nature Communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-38797-8
Publication status	Published - Jun 2023

Funding

Funding Information: The authors thank Samara Brown, current and previous Reiner and Hanna lab members. Merav Kedmi and Muriel Chemla from the Biological services; Current and ex-staff from the INCPM for help with the library prep and sequencing. Yungui Yang for assistance with sequencing at the Beijing genomics institute. Eran Hornstein and Eli Arama for helpful discussions. Phillip Sharp for the AGO mESCs. Orly Reiner is an incumbent of the Berstein-Mason professorial chair of Neurochemistry and the Head of the M. Judith Ruth Institute for Preclinical Brain Research. Our research has been supported by a research grant from Ethel Lena Levy, a research grant from the Estate of Olga Klein Astrachan, the Weizmann Gladys Monroy and Larry Marks Center for Brain Disorders, the Selsky Memory Research Project, the Advantage Trust, the William and Joan Brodsky Foundation and the Edward F. Anixter Family Foundation, the Helen and Martin Kimmel Institute for Stem Cell Research, the Kekst Center, the Nella and Leon Benoziyo Center for Neurological Diseases, the David and Fela Shapell Family Center for Genetic Disorders Research, the Brenden-Mann Women’s Innovation Impact Fund, The Irving B. Harris Fund for New Directions in Brain Research, the Irving Bieber, M.D. and Toby Bieber, M.D. Memorial Research Fund, The Leff Family, Barbara and Roberto Kaminitz, Sergio and Sônia Lozinsky, Debbie Koren, Jack Lowenthal, Lenore Lowenthal, and the Dears Foundation, the Estates of Norman Fidelman, and Hermine Miller, Debbie Koren, Jack, and Lenore Lowenthal, a research grant from the Weizmann SABRA—Yeda-Sela—WRC Program, the Estate of Emile Mimran, and The Maurice and Vivienne Wohl Biology Endowment Canadian Institutes of Health Research (CIHR), the International Development Research Centre (IDRC), the Israel Science Foundation (ISF) and the Azrieli Foundation (2397/18), the ISF grant (545/21), and the United States-Israel Binational Science Foundation (BSF; Grant No. 2017006). Publisher Copyright: © 2023, The Author(s).

All Science Journal Classification (ASJC) codes

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

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Kshirsagar, A., Doroshev, S. M., Gorelik, A., Olender, T., Sapir, T., Tsuboi, D., Rosenhek-Goldian, I., Malitsky, S., Itkin, M., Argoetti, A., Mandel-Gutfreund, Y., Cohen, S. R., Hanna, J. H., Ulitsky, I., Kaibuchi, K., & Reiner, O. (2023). LIS1 RNA-binding orchestrates the mechanosensitive properties of embryonic stem cells in AGO2-dependent and independent ways. Nature Communications, 14(1), Article 3293. https://doi.org/10.1038/s41467-023-38797-8

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

abstract = "Lissencephaly-1 (LIS1) is associated with neurodevelopmental diseases and is known to regulate the molecular motor cytoplasmic dynein activity. Here we show that LIS1 is essential for the viability of mouse embryonic stem cells (mESCs), and it governs the physical properties of these cells. LIS1 dosage substantially affects gene expression, and we uncovered an unexpected interaction of LIS1 with RNA and RNA-binding proteins, most prominently the Argonaute complex. We demonstrate that LIS1 overexpression partially rescued the extracellular matrix (ECM) expression and mechanosensitive genes conferring stiffness to Argonaute null mESCs. Collectively, our data transforms the current perspective on the roles of LIS1 in post-transcriptional regulation underlying development and mechanosensitive processes.",

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

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Kshirsagar, A, Doroshev, SM, Gorelik, A, Olender, T , Sapir, T, Tsuboi, D, Rosenhek-Goldian, I , Malitsky, S , Itkin, M, Argoetti, A, Mandel-Gutfreund, Y, Cohen, SR , Hanna, JH , Ulitsky, I, Kaibuchi, K & Reiner, O 2023, 'LIS1 RNA-binding orchestrates the mechanosensitive properties of embryonic stem cells in AGO2-dependent and independent ways', Nature Communications, vol. 14, no. 1, 3293. https://doi.org/10.1038/s41467-023-38797-8

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T1 - LIS1 RNA-binding orchestrates the mechanosensitive properties of embryonic stem cells in AGO2-dependent and independent ways

AU - Kshirsagar, Aditya

AU - Doroshev, Svetlana Maslov

AU - Gorelik, Anna

AU - Olender, Tsviya

AU - Sapir, Tamar

AU - Tsuboi, Daisuke

AU - Rosenhek-Goldian, Irit

AU - Malitsky, Sergey

AU - Itkin, Maxim

AU - Argoetti, Amir

AU - Mandel-Gutfreund, Yael

AU - Cohen, Sidney R.

AU - Hanna, Jacob H.

AU - Ulitsky, Igor

AU - Kaibuchi, Kozo

AU - Reiner, Orly

PY - 2023/6

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AB - Lissencephaly-1 (LIS1) is associated with neurodevelopmental diseases and is known to regulate the molecular motor cytoplasmic dynein activity. Here we show that LIS1 is essential for the viability of mouse embryonic stem cells (mESCs), and it governs the physical properties of these cells. LIS1 dosage substantially affects gene expression, and we uncovered an unexpected interaction of LIS1 with RNA and RNA-binding proteins, most prominently the Argonaute complex. We demonstrate that LIS1 overexpression partially rescued the extracellular matrix (ECM) expression and mechanosensitive genes conferring stiffness to Argonaute null mESCs. Collectively, our data transforms the current perspective on the roles of LIS1 in post-transcriptional regulation underlying development and mechanosensitive processes.

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

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