miR-409-3p represses Cited2 to refine neocortical layer V projection neuron identity
The evolutionary emergence of the corticospinal tract and corpus callosum are thought to underpin the expansion of complex motor and cognitive abilities in mammals. Molecular mechanisms regulating development of the neurons whose axons comprise these tracts, the corticospinal and callosal projection...
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| Format: | Article |
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Frontiers Media S.A.
2022-09-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnins.2022.931333/full |
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| author | Nikolaus R. Wagner Ashis Sinha Verl Siththanandan Angelica M. Kowalchuk Jessica L. MacDonald Suzanne Tharin Suzanne Tharin |
| author_facet | Nikolaus R. Wagner Ashis Sinha Verl Siththanandan Angelica M. Kowalchuk Jessica L. MacDonald Suzanne Tharin Suzanne Tharin |
| author_sort | Nikolaus R. Wagner |
| collection | DOAJ |
| description | The evolutionary emergence of the corticospinal tract and corpus callosum are thought to underpin the expansion of complex motor and cognitive abilities in mammals. Molecular mechanisms regulating development of the neurons whose axons comprise these tracts, the corticospinal and callosal projection neurons, remain incompletely understood. Our previous work identified a genomic cluster of microRNAs (miRNAs), Mirg/12qF1, that is unique to placental mammals and specifically expressed by corticospinal neurons, and excluded from callosal projection neurons, during development. We found that one of these, miR-409-3p, can convert layer V callosal into corticospinal projection neurons, acting in part through repression of the transcriptional regulator Lmo4. Here we show that miR-409-3p also directly represses the transcriptional co-regulator Cited2, which is highly expressed by callosal projection neurons from the earliest stages of neurogenesis. Cited2 is highly expressed by intermediate progenitor cells (IPCs) in the embryonic neocortex while Mirg, which encodes miR-409-3p, is excluded from these progenitors. miR-409-3p gain-of-function (GOF) in IPCs results in a phenocopy of established Cited2 loss-of-function (LOF). At later developmental stages, both miR-409-3p GOF and Cited2 LOF promote the expression of corticospinal at the expense of callosal projection neuron markers in layer V. Taken together, this work identifies previously undescribed roles for miR-409-3p in controlling IPC numbers and for Cited2 in controlling callosal fate. Thus, miR-409-3p, possibly in cooperation with other Mirg/12qF1 miRNAs, represses Cited2 as part of the multifaceted regulation of the refinement of neuronal cell fate within layer V, combining molecular regulation at multiple levels in both progenitors and post-mitotic neurons. |
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| id | doaj.art-79d7b588615e43ecb088e961edbc7f99 |
| institution | Directory Open Access Journal |
| issn | 1662-453X |
| language | English |
| last_indexed | 2024-04-12T18:07:22Z |
| publishDate | 2022-09-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Neuroscience |
| spelling | doaj.art-79d7b588615e43ecb088e961edbc7f992022-12-22T03:21:57ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2022-09-011610.3389/fnins.2022.931333931333miR-409-3p represses Cited2 to refine neocortical layer V projection neuron identityNikolaus R. Wagner0Ashis Sinha1Verl Siththanandan2Angelica M. Kowalchuk3Jessica L. MacDonald4Suzanne Tharin5Suzanne Tharin6Department of Biology, Program in Neuroscience, Syracuse University, Syracuse, NY, United StatesDepartment of Biology, Program in Neuroscience, Syracuse University, Syracuse, NY, United StatesDepartment of Neurosurgery, Stanford University Medical Center, Center for Academic Medicine, Palo Alto, CA, United StatesDepartment of Biology, Program in Neuroscience, Syracuse University, Syracuse, NY, United StatesDepartment of Biology, Program in Neuroscience, Syracuse University, Syracuse, NY, United StatesDepartment of Neurosurgery, Stanford University Medical Center, Center for Academic Medicine, Palo Alto, CA, United StatesDivision of Neurosurgery, Palo Alto Veterans Affairs Health Care System, Palo Alto, CA, United StatesThe evolutionary emergence of the corticospinal tract and corpus callosum are thought to underpin the expansion of complex motor and cognitive abilities in mammals. Molecular mechanisms regulating development of the neurons whose axons comprise these tracts, the corticospinal and callosal projection neurons, remain incompletely understood. Our previous work identified a genomic cluster of microRNAs (miRNAs), Mirg/12qF1, that is unique to placental mammals and specifically expressed by corticospinal neurons, and excluded from callosal projection neurons, during development. We found that one of these, miR-409-3p, can convert layer V callosal into corticospinal projection neurons, acting in part through repression of the transcriptional regulator Lmo4. Here we show that miR-409-3p also directly represses the transcriptional co-regulator Cited2, which is highly expressed by callosal projection neurons from the earliest stages of neurogenesis. Cited2 is highly expressed by intermediate progenitor cells (IPCs) in the embryonic neocortex while Mirg, which encodes miR-409-3p, is excluded from these progenitors. miR-409-3p gain-of-function (GOF) in IPCs results in a phenocopy of established Cited2 loss-of-function (LOF). At later developmental stages, both miR-409-3p GOF and Cited2 LOF promote the expression of corticospinal at the expense of callosal projection neuron markers in layer V. Taken together, this work identifies previously undescribed roles for miR-409-3p in controlling IPC numbers and for Cited2 in controlling callosal fate. Thus, miR-409-3p, possibly in cooperation with other Mirg/12qF1 miRNAs, represses Cited2 as part of the multifaceted regulation of the refinement of neuronal cell fate within layer V, combining molecular regulation at multiple levels in both progenitors and post-mitotic neurons.https://www.frontiersin.org/articles/10.3389/fnins.2022.931333/fullneocortical developmentneuronal cell fatecallosal projection neuroncorticospinal motor neuronmicroRNA |
| spellingShingle | Nikolaus R. Wagner Ashis Sinha Verl Siththanandan Angelica M. Kowalchuk Jessica L. MacDonald Suzanne Tharin Suzanne Tharin miR-409-3p represses Cited2 to refine neocortical layer V projection neuron identity Frontiers in Neuroscience neocortical development neuronal cell fate callosal projection neuron corticospinal motor neuron microRNA |
| title | miR-409-3p represses Cited2 to refine neocortical layer V projection neuron identity |
| title_full | miR-409-3p represses Cited2 to refine neocortical layer V projection neuron identity |
| title_fullStr | miR-409-3p represses Cited2 to refine neocortical layer V projection neuron identity |
| title_full_unstemmed | miR-409-3p represses Cited2 to refine neocortical layer V projection neuron identity |
| title_short | miR-409-3p represses Cited2 to refine neocortical layer V projection neuron identity |
| title_sort | mir 409 3p represses cited2 to refine neocortical layer v projection neuron identity |
| topic | neocortical development neuronal cell fate callosal projection neuron corticospinal motor neuron microRNA |
| url | https://www.frontiersin.org/articles/10.3389/fnins.2022.931333/full |
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