Key Points
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Alternative splicing explains how a single gene can generate more than one mRNA transcript, thus expanding the complexity of the proteome.
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During normal development, a large number of alternative splicing changes occur, and it is now apparent that these transitions between alternatively spliced isoforms contribute to the acquisition of adult tissue functions and identity.
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Individual splicing changes are coordinated during development, establishing splicing networks.
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As a result of recent progress, we now better understand the mechanisms that coordinate alternative splicing networks and the roles of these networks in cell differentiation, organ development and tissue homeostasis.
Abstract
Alternative splicing of eukaryotic transcripts is a mechanism that enables cells to generate vast protein diversity from a limited number of genes. The mechanisms and outcomes of alternative splicing of individual transcripts are relatively well understood, and recent efforts have been directed towards studying splicing networks. It has become apparent that coordinated splicing networks regulate tissue and organ development, and that alternative splicing has important physiological functions in different developmental processes in humans.
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Acknowledgements
J.G. is supported by start-up funds, a Junior Faculty Development Award and a Nutrition Obesity Research Center (NORC) Pilot and Feasibility Grant (P30DK056350) from The University of North Carolina at Chapel Hill.
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Supplementary information S1 (table)
RNA-binding proteins (RBPs) regulating alternative splicing in developmental or differentiation contexts (PDF 156 kb)
Glossary
- Spliceosome
-
A large, macromolecular complex composed of small nuclear RNAs and protein factors that removes regions (mostly introns) from transcribed precursor mRNA.
- RNA-binding proteins
-
(RBPs). Proteins that bind to RNA molecules through RNA-recognition motifs and exert nuclear and cytoplasmic post-transcriptional functions.
- Poison exons
-
Exons that, when included in mRNA, introduce a premature termination codon.
- Nonsense-mediated mRNA decay
-
(NMD). A regulatory mechanism that controls mRNA levels by eliminating mRNA transcripts that contain premature stop codons.
- Filamin A
-
An actin-binding protein that is involved in the crosslinking of actin filaments, cytoskeleton remodelling, cell shape and cell migration.
- Ninein
-
A protein involved in the anchoring of microtubule minus-ends and in centrosomal functions.
- Amyotrophic lateral sclerosis
-
A progressive neurodegenerative disease in which motor neuron functions are altered and motor neurons die. As a consequence, the brain is not capable of controlling muscle movement, and people with the disease lose the ability to speak, eat, move and breathe.
- Frontotemporal lobar degeneration
-
A disease caused by progressive damage to and atrophy of the temporal and/or frontal lobes of the brain.
- Z-Line
-
The line that separates two adjacent sarcomeres.
- M-Line
-
The centre of the sarcomere and the anchor site for thick myosin filaments.
- Sarcomere
-
The basic structural unit of a myofibril in striated muscles. The sarcomere consists of a dark band and the nearest half of the adjacent pale band. Sarcomeres are composed of myosin filaments (thick) and actin filaments (thin).
- Myoblast fusion
-
Myoblast cells fuse with each other, forming multinucleated myotubes that generate muscle fibres (myofibres) during development.
- c-Jun N-terminal kinase signalling cascade
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(JNK signalling cascade). A signalling pathway that is activated by environmental stress, inflammatory cytokines and growth factors. On its activation, JNK translocates to the nucleus, where it regulates transcription.
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Baralle, F., Giudice, J. Alternative splicing as a regulator of development and tissue identity. Nat Rev Mol Cell Biol 18, 437–451 (2017). https://doi.org/10.1038/nrm.2017.27
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DOI: https://doi.org/10.1038/nrm.2017.27
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