Lin28 promotes the proliferative capacity of neural progenitor cells in brain development
Open accessAbstract
Neural progenitor cells (NPCs) have distinct proliferation capacities at different stages of brain development. Lin28 is an RNA-binding protein with two homologs in mice: Lin28a and Lin28b. Here we show that Lin28a/b are enriched in early NPCs and their expression declines during neural differentiation. Lin28a single-knockout mice show reduced NPC proliferation, enhanced cell cycle exit and a smaller brain, whereas mice lacking both Lin28a alleles and one Lin28b allele display similar but more severe phenotypes. Ectopic expression of Lin28a in mice results in increased NPC proliferation, NPC numbers and brain size. Mechanistically, Lin28a physically and functionally interacts with Imp1 (Igf2bp1) and regulates Igf2-mTOR signaling. The function of Lin28a/b in NPCs could be attributed, at least in part, to the regulation of their mRNA targets that encode Igf1r and Hmga2. Thus, Lin28a and Lin28b have overlapping functions in temporally regulating NPC proliferation during early brain development.
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Gene expression analysis of cortical tissue showed robust down-regulation of LIN28B during midfetal cortical development in DS.
“Evidence for heterochrony in DS is revealed by gene expression analysis of cortical tissue that showed the robust down-regulation during midfetal cortical development of LIN28B, a gene that promotes proliferation of NPCs in a developmental, stage-specific manner and is one of the genes mutated in the original heterochronic C. elegans mutants39,150,151.”
From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [151]
The section on Lin28a deletion reports that Lin28a/b protein levels decline as the mouse cerebral cortex develops. The paper does not report gene-expression analysis of midfetal cortical tissue in Down syndrome or establish robust LIN28B down-regulation in DS; its evidence concerns a different species, condition, and measurement. (LLM, conf=0.86)
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References 46 · Cited by 127
Research works printed but not linked: 1
- Cimadamore, F., Amador-Arjona, A., Chen, C., Huang, C.-T. and Terskikh, A. V. (2013). SOX2-LIN28/let-7 pathway regulates proliferation and neurogenesis in neural precursors. Proc. Natl. Acad. Sci. USA 110, E3017-E3026.
- Authors
- Yang, M., Yang, S.-L., Herrlinger, S., Liang, C., Dzieciatkowska, M., Hansen, K. C., Desai, R., Nagy, A., Niswander, L., Moss, E. G., & Chen, J.-F.
- Affiliations
- University of Georgia (US)
- Department of Genetics, Biochemistry & Molecular Biology, University of Georgia, Athens, GA 30602, USA
- Department of Biochemistry & Molecular Genetics, University of Colorado Denver, Aurora, CO 80045, USA
- University of Colorado Denver (US)
- Mount Sinai Hospital (CA)
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5T 3L9, Canada
- Children's Hospital Colorado (US)
- Rowan University (US)
- Corresponding author
- Chen, Jian-Fu
- Venue
- Development
- Publisher
- The Company of Biologists
- Published
- 2015-05-01
- Volume
- 142
- Issue
- 9
- Pages
- 1616-1627
- ISSN
- 0950-1991 (ISSN-L)
- 1477-9129
- PMC
- PMC4419280
- OpenAlex
- W2328465532
- Cited by
- 127
- References
- 46
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 9 · 2023: 10 · 2022: 7 · 2021: 12 · 2020: 22 · 2019: 17 · 2018: 13 · 2017: 6 · 2016: 10 · 2015: 7
- FWCI
- 4.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (UL1TR000154, UL1TR001082)
- National Institute of Neurological Disorders and Stroke (P30NS048154, NS085749, R21NS085749, R01NS096176, R01NS097231)
- National Center for Advancing Translational Sciences
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R00HD073269, R01HD081562, K99HD073269, HD081562)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Keywords
- LIN28A, LIN28B, neural progenitor cells, cell proliferation, brain development, IGF-1 receptor, HMGA2, RNA-binding proteins, neuronal differentiation, cell cycle exit, brain size, knockout mice
- MeSH terms
- Animals, Brain, Bromodeoxyuridine, DNA-Binding Proteins, RNA-Binding Proteins, Electroporation, Mice, Knockout, Gene Expression Regulation, Developmental, HMGA2 Protein, Immunoprecipitation, Cell Proliferation, Mice, Neural Stem Cells, Real-Time Polymerase Chain Reaction
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