Abstract
Adult neurogenesis is primarily directed by neural progenitor cells, which reside in the subventricular zone (SVZ) and subgranular zone (SGZ) of the brain. Unfolding transcriptional heterogeneity and complexity of various neurodevelopmental stages can probe new insights into neurogenesis and neurodevelopmental disorders. Recent findings have suggested that epigenetic regulatory mechanisms in neural differentiation involve long noncoding RNAs (lncRNAs) as a new genre of regulators. Although many studies have addressed the overall consequences of the noncoding RNome (noncoding RNA content) on the genome, lesser is known about their specific roles and consequences in adult neurogenesis, neurodevelopmental stages, and onset of neuropathology. Recent advances in induced pluripotent stem cell (iPSC)-based neurological disease modeling have shed light on new avenues to investigate neuronal development as well as molecular paradigms underlying onset of neurological impairments. However, due to limited availability of brain tissues and gap in the understanding of lncRNA biomarkers in neurodevelopment, the study of lncRNA in neurogenesis still exists at its infancy. To further understand the lncRNA-mediated regulation in stage-specific development of pluripotent stem cell-derived neurons and other brain cells, we identified potential lncRNA signatures implicative in brain development or dysregulation using data mining and analyses. They may be used in monitoring disease progression and may serve as potential targets for novel therapeutic approaches.
Abbreviations
- AP:
-
Anteroposterior
- DA:
-
Dopaminergic
- DCX:
-
Doublecortin
- DG:
-
Dentate gyrus
- EB:
-
Embryonic body
- hESCs:
-
Human embryonic stem cells
- iPSCs:
-
Induced pluripotent stem cells
- lncRNAs:
-
Long noncoding RNAs
- NECs:
-
Neuroepithelial cells
- NGS:
-
Next-generation sequencing
- NPCs:
-
Neural progenitor cells
- PSA-NCAM:
-
Polysialylated neural cell adhesion molecule
- SGZ:
-
Subgranular zone
- snoRNAs:
-
Small noncoding RNAs
References
Cameron HA, Hazel TG, McKay RD. Regulation of neurogenesis by growth factors and neurotransmitters. J Neurobiol. 1998;36(2):287–306.
Nicola Z, Fabel K, Kempermann G. Development of the adult neurogenic niche in the hippocampus of mice. Front Neuroanat. 2015;9:53.
Spalding KL, et al. Dynamics of hippocampal neurogenesis in adult humans. Cell. 2013;153(6):1219–27.
Ninkovic J, Götz M. Signaling in adult neurogenesis: from stem cell niche to neuronal networks. Curr Opin Neurobiol. 2007;17(3):338–44.
Imayoshi I, et al. Roles of continuous neurogenesis in the structural and functional integrity of the adult forebrain. Nat Neurosci. 2008;11(10):1153–61.
Ernst A, et al. Neurogenesis in the striatum of the adult human brain. Cell. 2014;156(5):1072–83.
Supeno NE, et al. IGF-1 acts as controlling switch for long-term proliferation and maintenance of EGF/FGF-responsive striatal neural stem cells. Int J Med Sci. 2013;10(5):522–31.
Liu H, Song N. Molecular mechanism of adult neurogenesis and its association with human brain diseases. J Cent Nerv Syst Dis. 2016;8:5–11.
Ming G-l, Song H. DISC1 partners with GSK3β in neurogenesis. Cell. 2009;136(6):990–2.
Nakagawa M, et al. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol. 2008;26(1):101–6.
Rinn JL, Chang HY. Genome regulation by long noncoding RNAs. Annu Rev Biochem. 2012;81:145–66.
Knauss JL, Sun T. Regulatory mechanisms of long noncoding RNAs in vertebrate central nervous system development and function. Neuroscience. 2013;235:200–14.
Pannese E. The black reaction. Brain Res Bull. 1996;41(6):343–9.
Altman J, Das GD. Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol. 1965;124(3):319–35.
Eriksson PS, et al. Neurogenesis in the adult human hippocampus. Nat Med. 1998;4(11):1313–7.
Reynolds BA, Weiss S. Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science. 1992;255(5052):1707.
Richards L, Kilpatrick T, Bartlett P. De novo generation of neuronal cells from the adult mouse brain. Proc Natl Acad Sci. 1992;89(18):8591–5.
NOTTEBOHM F. The road we travelled: discovery, choreography, and significance of brain replaceable neurons. Ann N Y Acad Sci. 2004;1016(1):628–58.
Seki T, Arai Y. Highly polysialylated neural cell adhesion molecule (NCAM-H) is expressed by newly generated granule cells in the dentate gyrus of the adult rat. J Neurosci. 1993;13(6):2351–8.
Deng X-Y, et al. Non-viral methods for generating integration-free, induced pluripotent stem cells. Curr Stem Cell Res Ther. 2015;10(2):153–8.
Devito L, et al. Cost-effective master cell bank validation of multiple clinical-grade human pluripotent stem cell lines from a single donor. Stem Cells Transl Med. 2014;3(10):1116–24.
Wang J, et al. Generation of clinical-grade human induced pluripotent stem cells in Xeno-free conditions. Stem Cell Res Ther. 2015;6(1):1.
Grskovic M, et al. Induced pluripotent stem cells—opportunities for disease modelling and drug discovery. Nat Rev Drug Discov. 2011;10(12):915–29.
Kálmán S, Hathy E, Réthelyi JM. A dishful of a troubled mind: induced pluripotent stem cells in psychiatric research. Stem Cells Int. 2016;2016:7909176.
Maury Y, et al. Human pluripotent stem cells for disease modelling and drug screening. BioEssays. 2012;34(1):61–71.
Meneghello G, et al. Evaluation of established human iPSC-derived neurons to model neurodegenerative diseases. Neuroscience. 2015;301:204–12.
Thiruvalluvan A, et al. Survival and functionality of human induced pluripotent stem cell-derived oligodendrocytes in a nonhuman primate model for multiple sclerosis. Stem Cells Transl Med. 2016;5(11):1550–61.
Zhou S, et al. The positional identity of iPSC-derived neural progenitor cells along the anterior-posterior axis is controlled in a dosage-dependent manner by bFGF and EGF. Differentiation. 2016;92(4):183–94.
Zhou S, et al. Neurosphere based differentiation of human iPSC improves astrocyte differentiation. Stem Cells Int. 2015;2016:4937689.
Liyang G, et al. Neural commitment of embryonic stem cells through the formation of embryoid bodies (EBs). MalaysJ Med Sci. 2014;21(5):8.
Pettinato G, Wen X, Zhang N. Formation of well-defined embryoid bodies from dissociated human induced pluripotent stem cells using microfabricated cell-repellent microwell arrays. Sci Rep. 2014;4:7402.
Cho E-G, et al. MEF2C enhances dopaminergic neuron differentiation of human embryonic stem cells in a parkinsonian rat model. PLoS One. 2011;6(8):e24027.
Elkabetz Y, et al. Human ES cell-derived neural rosettes reveal a functionally distinct early neural stem cell stage. Genes Dev. 2008;22(2):152–65.
Schulz TC, et al. Directed neuronal differentiation of human embryonic stem cells. BMC Neurosci. 2003;4(1):1.
Boissart C, et al. miR-125 potentiates early neural specification of human embryonic stem cells. Development. 2012;139(7):1247–57.
Chambers SM, et al. Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat Biotechnol. 2009;27(3):275–80.
Pombero A, Martinez S. Telencephalic morphogenesis during the process of neurulation: An experimental study using quail–chick chimeras. J Comp Neurol. 2009;512(6):784–97.
Vieira C, et al. Molecular mechanisms controlling brain development: an overview of neuroepithelial secondary organizers. Int J Dev Biol. 2009;54(1):7–20.
Li X-J, et al. Coordination of sonic hedgehog and Wnt signaling determines ventral and dorsal telencephalic neuron types from human embryonic stem cells. Development. 2009;136(23):4055–63.
Zeng H, et al. Specification of region-specific neurons including forebrain glutamatergic neurons from human induced pluripotent stem cells. PLoS One. 2010;5(7):e11853.
Carri AD, et al. Developmentally coordinated extrinsic signals drive human pluripotent stem cell differentiation toward authentic DARPP-32+ medium-sized spiny neurons. Development. 2013;140(2):301–12.
Maroof AM, et al. Directed differentiation and functional maturation of cortical interneurons from human embryonic stem cells. Cell Stem Cell. 2013;12(5):559–72.
Friling S, et al. Efficient production of mesencephalic dopamine neurons by Lmx1a expression in embryonic stem cells. Proc Natl Acad Sci. 2009;106(18):7613–8.
Rhee Y-H, et al. Protein-based human iPS cells efficiently generate functional dopamine neurons and can treat a rat model of Parkinson disease. J Clin Invest. 2011;121(6):2326–35.
Kirkeby A, et al. Generation of regionally specified neural progenitors and functional neurons from human embryonic stem cells under defined conditions. Cell Rep. 2012;1(6):703–14.
Kriks S, et al. Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson/'s disease. Nature. 2011;480(7378):547–51.
Codega P, et al. Prospective identification and purification of quiescent adult neural stem cells from their in vivo niche. Neuron. 2014;82(3):545–59.
Koch P, et al. A rosette-type, self-renewing human ES cell-derived neural stem cell with potential for in vitro instruction and synaptic integration. Proc Natl Acad Sci U S A. 2009;106(9):3225–30.
Shi Y, et al. Human cerebral cortex development from pluripotent stem cells to functional excitatory synapses. Nat Neurosci. 2012;15(3):477–86.
Espuny-Camacho I, et al. Pyramidal neurons derived from human pluripotent stem cells integrate efficiently into mouse brain circuits in vivo. Neuron. 2013;77(3):440–56.
Vazin T, et al. Efficient derivation of cortical glutamatergic neurons from human pluripotent stem cells: a model system to study neurotoxicity in Alzheimer's disease. Neurobiol Dis. 2014;62:62–72.
Hartfield EM, et al. Physiological characterisation of human iPS-derived dopaminergic neurons. PLoS One. 2014;9(2):e87388.
Bissonnette CJ, et al. The controlled generation of functional basal forebrain cholinergic neurons from human embryonic stem cells. Stem Cells. 2011;29(5):802–11.
Hu B-Y, Du Z-W, Zhang S-C. Differentiation of human oligodendrocytes from pluripotent stem cells. Nat Protoc. 2009;4(11):1614–22.
MarÃn O, Rubenstein JL. A long, remarkable journey: tangential migration in the telencephalon. Nat Rev Neurosci. 2001;2(11):780–90.
Lancaster MA, Knoblich JA. Generation of cerebral organoids from human pluripotent stem cells. Nat Protoc. 2014;9(10):2329–40.
Pollard KS, et al. An RNA gene expressed during cortical development evolved rapidly in humans. Nature. 2006;443(7108):167–72.
Dinger ME, et al. Long noncoding RNAs in mouse embryonic stem cell pluripotency and differentiation. Genome Res. 2008;18(9):1433–45.
Luo H, et al. Comprehensive characterization of 10,571 mouse large intergenic noncoding RNAs from whole transcriptome sequencing. PLoS One. 2013;8(8):e70835.
Wang L, et al. Regulation of neuronal-glial fate specification by long non-coding RNAs. Rev Neurosci. 2016;27(5):491–9.
Amaral PP, et al. Complex architecture and regulated expression of the Sox2ot locus during vertebrate development. RNA. 2009;15(11):2013–27.
Mercer TR, et al. Specific expression of long noncoding RNAs in the mouse brain. Proc Natl Acad Sci. 2008;105(2):716–21.
Ramos AD, et al. The long noncoding RNA Pnky regulates neuronal differentiation of embryonic and postnatal neural stem cells. Cell Stem Cell. 2015;16(4):439–47.
Tochitani S, Hayashizaki Y. Nkx2.2 antisense RNA overexpression enhanced oligodendrocytic differentiation. Biochem Biophys Res Commun. 2008;372(4):691–6.
Price M, et al. Regional expression of the homeobox gene Nkx-2.2 in the developing mammalian forebrain. Neuron. 1992;8(2):241–55.
Sunkin SM, et al. Allen Brain Atlas: an integrated spatio-temporal portal for exploring the central nervous system. Nucleic Acids Res. 2013;41(D1):D996–D1008.
Carninci P, et al. The transcriptional landscape of the mammalian genome. Science. 2005;309(5740):1559–63.
Ponjavic J, et al. Genomic and transcriptional co-localization of protein-coding and long non-coding RNA pairs in the developing brain. PLoS Genet. 2009;5(8):e1000617.
Guttman M, et al. Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature. 2009;458(7235):223–7.
Mercer TR, et al. Long noncoding RNAs in neuronal-glial fate specification and oligodendrocyte lineage maturation. BMC Neurosci. 2010;11(1):1–15.
Ramos AD, et al. Integration of genome-wide approaches identifies lncRNAs of adult neural stem cells and their progeny in vivo. Cell Stem Cell. 2013;12(5):616–28.
Mattick JS. RNA regulation: a new genetics? Nat Rev Genet. 2004;5(4):316–23.
The EPC. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012;489(7414):57–74.
Yan D, et al. Identification and analysis of intermediate size noncoding RNAs in the human fetal brain. PLoS One. 2011;6(7):e21652.
Mercer TR, et al. Specific expression of long noncoding RNAs in the mouse brain. Proc Natl Acad Sci U S A. 2008;105(2):716–21.
Lai F, et al. Activating RNAs associate with mediator to enhance chromatin architecture and transcription. Nature. 2013;494(7438):497–501.
Hacisuleyman E, et al. Topological organization of multichromosomal regions by the long intergenic noncoding RNA Firre. Nat Struct Mol Biol. 2014;21(2):198–206.
Spector DL, Lamond AI. Nuclear speckles. Cold Spring Harb Perspect Biol. 2011;3(2):a000646.
Clemson CM, et al. An architectural role for a nuclear noncoding RNA: NEAT1 RNA is essential for the structure of paraspeckles. Mol Cell. 2009;33:717–26.
Tripathi V, et al. The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation. Mol Cell. 2010;39(6):925–38.
Yoon J-H, et al. Scaffold function of long non-coding RNA HOTAIR in protein ubiquitination. Nat Commun. 2013;4:2939.
Guil S, et al. Intronic RNAs mediate EZH2 regulation of epigenetic targets. Nat Struct Mol Biol. 2012;19(7):664–70.
Tsai MC, et al. Long noncoding RNA as modular scaffold of histone modification complexes. Science. 2010;329(5992):689–93.
Zhao J, et al. Polycomb proteins targeted by a short repeat RNA to the mouse X chromosome. Science. 2008;322(5902):750–6.
Keller C, et al. Noncoding RNAs prevent spreading of a repressive histone mark. Nat Struct Mol Biol. 2013;20(8):994–1000.
Lister R, et al. Global epigenomic reconfiguration during mammalian brain development. Science. 2013;341(6146):1237905.
D’haene E, et al. Identification of long non-coding RNAs involved in neuronal development and intellectual disability. Sci Rep. 2016;6:28396.
Jenuwein T, Allis CD. Translating the histone code. Science. 2001;293(5532):1074–80.
Nagano T, et al. The air noncoding RNA epigenetically silences transcription by targeting G9a to chromatin. Science. 2008;322(5908):1717–20.
Pandey RR, et al. Kcnq1ot1 antisense noncoding RNA mediates lineage-specific transcriptional silencing through chromatin-level regulation. Mol Cell. 2008;32(2):232–46.
van Heesch S, et al. Extensive localization of long noncoding RNAs to the cytosol and mono-and polyribosomal complexes. Genome Biol. 2014;15(1):1.
Yu J, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007;318(5858):1917–20.
Ng SY, Johnson R, Stanton LW. Human long non-coding RNAs promote pluripotency and neuronal differentiation by association with chromatin modifiers and transcription factors. EMBO J. 2012;31(3):522–33.
Mohamed JS, et al. Conserved long noncoding RNAs transcriptionally regulated by Oct4 and Nanog modulate pluripotency in mouse embryonic stem cells. RNA. 2010;16(2):324–37.
Lin N, et al. An evolutionarily conserved long noncoding RNA TUNA controls pluripotency and neural lineage commitment. Mol Cell. 2014;53(6):1005–19.
Ng SY, et al. The long noncoding RNA RMST interacts with SOX2 to regulate neurogenesis. Mol Cell. 2013;51(3):349–59.
Onoguchi M, et al. A noncoding RNA regulates the neurogenin1 gene locus during mouse neocortical development. Proc Natl Acad Sci U S A. 2012;109(42):16939–44.
Bernard D, et al. A long nuclear-retained non-coding RNA regulates synaptogenesis by modulating gene expression. EMBO J. 2010;29(18):3082–93.
Bond AM, et al. Balanced gene regulation by an embryonic brain ncRNA is critical for adult hippocampal GABA circuitry. Nat Neurosci. 2009;12(8):1020–7.
Rapicavoli NA, Poth EM, Blackshaw S. The long noncoding RNA RNCR2 directs mouse retinal cell specification. BMC Dev Biol. 2010;10:49.
Lin M, et al. RNA-Seq of human neurons derived from iPS cells reveals candidate long non-coding RNAs involved in neurogenesis and neuropsychiatric disorders. PLoS One. 2011;6(9):e23356.
Mo C-F, et al. Loss of non-coding RNA expression from the DLK1-DIO3 imprinted locus correlates with reduced neural differentiation potential in human embryonic stem cell lines. Stem Cell Res Ther. 2015;6(1):1.
Acknowledgments
The authors acknowledge R. Ayana, Ph.D. fellow of the Department of Life Sciences, Shiv Nadar University, India, for the original illustrations depicting adult neurogenesis. The authors have no conflict of interest.
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Pati, S., Singh, S. (2017). Unraveling the Role of Long Noncoding RNAs in Pluripotent Stem Cell-Based Neuronal Commitment and Neurogenesis. In: Mukhopadhyay, A. (eds) Regenerative Medicine: Laboratory to Clinic. Springer, Singapore. https://doi.org/10.1007/978-981-10-3701-6_3
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