hsa-let-7c miRNA Regulates Synaptic and Neuronal Function in Human Neurons
Non-coding RNA, including microRNA (miRNA) serves critical regulatory functions in the developing brain. The let-7 family of miRNAs has been shown to regulate neuronal differentiation, neural subtype specification, and synapse formation in animal models. However, the regulatory role of human let-7c...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-07-01
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| Series: | Frontiers in Synaptic Neuroscience |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fnsyn.2018.00019/full |
| _version_ | 1818973787685650432 |
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| author | Heather McGowan Heather McGowan Vincent R. Mirabella Vincent R. Mirabella Aula Hamod Aula Hamod Aziz Karakhanyan Aziz Karakhanyan Nicole Mlynaryk Nicole Mlynaryk Jennifer C. Moore Jay A. Tischfield Ronald P. Hart Zhiping P. Pang Zhiping P. Pang |
| author_facet | Heather McGowan Heather McGowan Vincent R. Mirabella Vincent R. Mirabella Aula Hamod Aula Hamod Aziz Karakhanyan Aziz Karakhanyan Nicole Mlynaryk Nicole Mlynaryk Jennifer C. Moore Jay A. Tischfield Ronald P. Hart Zhiping P. Pang Zhiping P. Pang |
| author_sort | Heather McGowan |
| collection | DOAJ |
| description | Non-coding RNA, including microRNA (miRNA) serves critical regulatory functions in the developing brain. The let-7 family of miRNAs has been shown to regulate neuronal differentiation, neural subtype specification, and synapse formation in animal models. However, the regulatory role of human let-7c (hsa-let-7c) in human neuronal development has yet to be examined. Let-7c is encoded on chromosome 21 in humans and therefore may be overexpressed in human brains in Trisomy 21 (T21), a complex neurodevelopmental disorder. Here, we employ recent developments in stem cell biology to show that hsa-let-7c mediates important regulatory epigenetic functions that control the development and functional activity of human induced neuronal cells (iNs). We show that overexpression of hsa-let-7c in human iNs derived from induced pluripotent stem (iPS), as well as embryonic stem (ES), cells leads to morphological as well as functional deficits including impaired neuronal morphologic development, synapse formation and synaptic strength, as well as a marked reduction of neuronal excitability. Importantly, we have assessed these findings over three independent genetic backgrounds, showing that some of these effects are subject to influence by background genetic variability with the most robust and reproducible effect being a striking reduction in spontaneous neural firing. Collectively, these results suggest an important function for let-7 family miRNAs in regulation of human neuronal development and raise implications for understanding the complex molecular etiology of neurodevelopmental disorders, such as T21, where let-7c gene dosage is increased. |
| first_indexed | 2024-12-20T15:29:43Z |
| format | Article |
| id | doaj.art-76ab7ffd7940456480c2b11fdad298d2 |
| institution | Directory Open Access Journal |
| issn | 1663-3563 |
| language | English |
| last_indexed | 2024-12-20T15:29:43Z |
| publishDate | 2018-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Synaptic Neuroscience |
| spelling | doaj.art-76ab7ffd7940456480c2b11fdad298d22022-12-21T19:35:40ZengFrontiers Media S.A.Frontiers in Synaptic Neuroscience1663-35632018-07-011010.3389/fnsyn.2018.00019377033hsa-let-7c miRNA Regulates Synaptic and Neuronal Function in Human NeuronsHeather McGowan0Heather McGowan1Vincent R. Mirabella2Vincent R. Mirabella3Aula Hamod4Aula Hamod5Aziz Karakhanyan6Aziz Karakhanyan7Nicole Mlynaryk8Nicole Mlynaryk9Jennifer C. Moore10Jay A. Tischfield11Ronald P. Hart12Zhiping P. Pang13Zhiping P. Pang14Child Health Institute of New Jersey, New Brunswick, NJ, United StatesDepartment of Neuroscience and Cell Biology, Rutgers University, Piscataway, NJ, United StatesChild Health Institute of New Jersey, New Brunswick, NJ, United StatesDepartment of Neuroscience and Cell Biology, Rutgers University, Piscataway, NJ, United StatesChild Health Institute of New Jersey, New Brunswick, NJ, United StatesDepartment of Neuroscience and Cell Biology, Rutgers University, Piscataway, NJ, United StatesChild Health Institute of New Jersey, New Brunswick, NJ, United StatesDepartment of Neuroscience and Cell Biology, Rutgers University, Piscataway, NJ, United StatesChild Health Institute of New Jersey, New Brunswick, NJ, United StatesDepartment of Neuroscience and Cell Biology, Rutgers University, Piscataway, NJ, United StatesDepartment of Genetics, Rutgers University, Piscataway, NJ, United StatesDepartment of Genetics, Rutgers University, Piscataway, NJ, United StatesDepartment of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, United StatesChild Health Institute of New Jersey, New Brunswick, NJ, United StatesDepartment of Neuroscience and Cell Biology, Rutgers University, Piscataway, NJ, United StatesNon-coding RNA, including microRNA (miRNA) serves critical regulatory functions in the developing brain. The let-7 family of miRNAs has been shown to regulate neuronal differentiation, neural subtype specification, and synapse formation in animal models. However, the regulatory role of human let-7c (hsa-let-7c) in human neuronal development has yet to be examined. Let-7c is encoded on chromosome 21 in humans and therefore may be overexpressed in human brains in Trisomy 21 (T21), a complex neurodevelopmental disorder. Here, we employ recent developments in stem cell biology to show that hsa-let-7c mediates important regulatory epigenetic functions that control the development and functional activity of human induced neuronal cells (iNs). We show that overexpression of hsa-let-7c in human iNs derived from induced pluripotent stem (iPS), as well as embryonic stem (ES), cells leads to morphological as well as functional deficits including impaired neuronal morphologic development, synapse formation and synaptic strength, as well as a marked reduction of neuronal excitability. Importantly, we have assessed these findings over three independent genetic backgrounds, showing that some of these effects are subject to influence by background genetic variability with the most robust and reproducible effect being a striking reduction in spontaneous neural firing. Collectively, these results suggest an important function for let-7 family miRNAs in regulation of human neuronal development and raise implications for understanding the complex molecular etiology of neurodevelopmental disorders, such as T21, where let-7c gene dosage is increased.https://www.frontiersin.org/article/10.3389/fnsyn.2018.00019/fullnon-coding RNAmicroRNAsynaptic transmissionhuman neuronsstem cells |
| spellingShingle | Heather McGowan Heather McGowan Vincent R. Mirabella Vincent R. Mirabella Aula Hamod Aula Hamod Aziz Karakhanyan Aziz Karakhanyan Nicole Mlynaryk Nicole Mlynaryk Jennifer C. Moore Jay A. Tischfield Ronald P. Hart Zhiping P. Pang Zhiping P. Pang hsa-let-7c miRNA Regulates Synaptic and Neuronal Function in Human Neurons Frontiers in Synaptic Neuroscience non-coding RNA microRNA synaptic transmission human neurons stem cells |
| title | hsa-let-7c miRNA Regulates Synaptic and Neuronal Function in Human Neurons |
| title_full | hsa-let-7c miRNA Regulates Synaptic and Neuronal Function in Human Neurons |
| title_fullStr | hsa-let-7c miRNA Regulates Synaptic and Neuronal Function in Human Neurons |
| title_full_unstemmed | hsa-let-7c miRNA Regulates Synaptic and Neuronal Function in Human Neurons |
| title_short | hsa-let-7c miRNA Regulates Synaptic and Neuronal Function in Human Neurons |
| title_sort | hsa let 7c mirna regulates synaptic and neuronal function in human neurons |
| topic | non-coding RNA microRNA synaptic transmission human neurons stem cells |
| url | https://www.frontiersin.org/article/10.3389/fnsyn.2018.00019/full |
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