The function of FUS in neurodevelopment revealed by the brain and spinal cord organoids

Huan Zou; Jun-Ying Wang; Guo-Ming Ma; Mei-Mei Xu; Fang Luo; Lin Zhang; Wen-Yuan Wang

doi:10.1016/j.mcn.2022.103771

The function of FUS in neurodevelopment revealed by the brain and spinal cord organoids

Mol Cell Neurosci. 2022 Dec:123:103771. doi: 10.1016/j.mcn.2022.103771. Epub 2022 Sep 3.

Authors

Huan Zou¹, Jun-Ying Wang¹, Guo-Ming Ma¹, Mei-Mei Xu¹, Fang Luo², Lin Zhang³, Wen-Yuan Wang⁴

Affiliations

¹ Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, Shanghai 200032, China; University of Chinese Academy of Sciences, Beijing 100049, China.
² Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, Shanghai 200032, China.
³ Obstetrics Department, International Peace Maternity and Child Health Hospital of China, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁴ Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, Shanghai 200032, China; Department of Rehabilitation Medicine, Hua-Shan Hospital, Fudan University, Shanghai 200040, China; Animal Center of Zoology, Institute of Neuroscience, Kunming medical University, Kunming, China. Electronic address: wywang@sioc.ac.cn.

PMID: 36064132
DOI: 10.1016/j.mcn.2022.103771

Abstract

The precise control of proliferation and differentiation of neural progenitors is crucial for the development of the central nervous system. Fused in sarcoma (FUS) is an RNA-binding protein pathogenetically linked to Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD) disease, yet the function of FUS on neurodevelopment is remained to be defined. Here we report a pivotal role of FUS in regulating the human cortical brain and spinal cord development via the human iPSCs-derived organoids. We found that depletion of FUS via CRISPR/CAS9 leads to an enhancement of neural proliferation and differentiation in cortical brain-organoids, but intriguingly an impairment of these phenotypes in spinal cord-organoids. In addition, FUS binds to the mRNA of a Trk tyrosine kinase receptor of neurotrophin-3 (Ntrk3) and regulates the expression of the different isoforms of Ntrk3 in a tissue-specific manner. Finally, alleviated Ntrk3 level via shRNA rescued the effects of FUS-knockout on the development of the brain- and spinal cord-organoids, suggesting that Ntrk3 is involved in FUS-regulated organoids developmental changes. Our findings uncovered the role of FUS in the neurodevelopment of the human CNS.

Keywords: Brain cortex; FUS; Organoids; Spinal cord; hiPSC.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amyotrophic Lateral Sclerosis* / metabolism
Brain / metabolism
Frontotemporal Lobar Degeneration* / genetics
Humans
Inclusion Bodies / metabolism
Organoids / metabolism
RNA-Binding Protein FUS / genetics
RNA-Binding Protein FUS / metabolism
Spinal Cord / metabolism

Substances

RNA-Binding Protein FUS
FUS protein, human