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1.
Dev Biol ; 478: 102-121, 2021 10.
Article in English | MEDLINE | ID: mdl-34181916

ABSTRACT

Human organoids stand at the forefront of basic and translational research, providing experimentally tractable systems to study human development and disease. These stem cell-derived, in vitro cultures can generate a multitude of tissue and organ types, including distinct brain regions and sensory systems. Neural organoid systems have provided fundamental insights into molecular mechanisms governing cell fate specification and neural circuit assembly and serve as promising tools for drug discovery and understanding disease pathogenesis. In this review, we discuss several human neural organoid systems, how they are generated, advances in 3D imaging and bioengineering, and the impact of organoid studies on our understanding of the human nervous system.


Subject(s)
Brain Diseases , Brain , Organoids , Retina , Brain/cytology , Brain/embryology , Brain/growth & development , Cell Differentiation , Developmental Biology/methods , Embryoid Bodies/physiology , Embryonic Induction , Humans , Neural Stem Cells/physiology , Neurobiology/methods , Neurogenesis , Retina/cytology , Retina/embryology , Retina/growth & development , Tissue Culture Techniques
2.
Mol Cell ; 77(1): 82-94.e4, 2020 01 02.
Article in English | MEDLINE | ID: mdl-31630970

ABSTRACT

FUS is a nuclear RNA-binding protein, and its cytoplasmic aggregation is a pathogenic signature of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). It remains unknown how the FUS-RNA interactions contribute to phase separation and whether its phase behavior is affected by ALS-linked mutations. Here we demonstrate that wild-type FUS binds single-stranded RNA stoichiometrically in a length-dependent manner and that multimers induce highly dynamic interactions with RNA, giving rise to small and fluid condensates. In contrast, mutations in arginine display a severely altered conformation, static binding to RNA, and formation of large condensates, signifying the role of arginine in driving proper RNA interaction. Glycine mutations undergo rapid loss of fluidity, emphasizing the role of glycine in promoting fluidity. Strikingly, the nuclear import receptor Karyopherin-ß2 reverses the mutant defects and recovers the wild-type FUS behavior. We reveal two distinct mechanisms underpinning potentially disparate pathogenic pathways of ALS-linked FUS mutants.


Subject(s)
Amyotrophic Lateral Sclerosis/genetics , Frontotemporal Dementia/genetics , Mutation/genetics , RNA-Binding Protein FUS/genetics , RNA/genetics , Active Transport, Cell Nucleus/genetics , Glycine/genetics , Humans
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