Isl1 directly controls a cholinergic neuronal identity in the developing forebrain and spinal cord by forming cell type-specific complexes.
The establishment of correct neurotransmitter characteristics is an essential step of neuronal fate specification in CNS development. However, very little is known about how a battery of genes involved in the determination of a specific type of chemical-driven neurotransmission is coordinately regul...
Saved in:
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2014-04-01
|
| Series: | PLoS Genetics |
| Online Access: | https://doi.org/10.1371/journal.pgen.1004280 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849726765664043008 |
|---|---|
| author | Hyong-Ho Cho Francesca Cargnin Yujin Kim Bora Lee Ryuk-Jun Kwon Heejin Nam Rongkun Shen Anthony P Barnes Jae W Lee Seunghee Lee Soo-Kyung Lee |
| author_facet | Hyong-Ho Cho Francesca Cargnin Yujin Kim Bora Lee Ryuk-Jun Kwon Heejin Nam Rongkun Shen Anthony P Barnes Jae W Lee Seunghee Lee Soo-Kyung Lee |
| author_sort | Hyong-Ho Cho |
| collection | DOAJ |
| description | The establishment of correct neurotransmitter characteristics is an essential step of neuronal fate specification in CNS development. However, very little is known about how a battery of genes involved in the determination of a specific type of chemical-driven neurotransmission is coordinately regulated during vertebrate development. Here, we investigated the gene regulatory networks that specify the cholinergic neuronal fates in the spinal cord and forebrain, specifically, spinal motor neurons (MNs) and forebrain cholinergic neurons (FCNs). Conditional inactivation of Isl1, a LIM homeodomain factor expressed in both differentiating MNs and FCNs, led to a drastic loss of cholinergic neurons in the developing spinal cord and forebrain. We found that Isl1 forms two related, but distinct types of complexes, the Isl1-Lhx3-hexamer in MNs and the Isl1-Lhx8-hexamer in FCNs. Interestingly, our genome-wide ChIP-seq analysis revealed that the Isl1-Lhx3-hexamer binds to a suite of cholinergic pathway genes encoding the core constituents of the cholinergic neurotransmission system, such as acetylcholine synthesizing enzymes and transporters. Consistently, the Isl1-Lhx3-hexamer directly coordinated upregulation of cholinergic pathways genes in embryonic spinal cord. Similarly, in the developing forebrain, the Isl1-Lhx8-hexamer was recruited to the cholinergic gene battery and promoted cholinergic gene expression. Furthermore, the expression of the Isl1-Lhx8-complex enabled the acquisition of cholinergic fate in embryonic stem cell-derived neurons. Together, our studies show a shared molecular mechanism that determines the cholinergic neuronal fate in the spinal cord and forebrain, and uncover an important gene regulatory mechanism that directs a specific neurotransmitter identity in vertebrate CNS development. |
| format | Article |
| id | doaj-art-5ceb7328a8aa40358e08268dbe756a07 |
| institution | DOAJ |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2014-04-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-5ceb7328a8aa40358e08268dbe756a072025-08-20T03:10:05ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042014-04-01104e100428010.1371/journal.pgen.1004280Isl1 directly controls a cholinergic neuronal identity in the developing forebrain and spinal cord by forming cell type-specific complexes.Hyong-Ho ChoFrancesca CargninYujin KimBora LeeRyuk-Jun KwonHeejin NamRongkun ShenAnthony P BarnesJae W LeeSeunghee LeeSoo-Kyung LeeThe establishment of correct neurotransmitter characteristics is an essential step of neuronal fate specification in CNS development. However, very little is known about how a battery of genes involved in the determination of a specific type of chemical-driven neurotransmission is coordinately regulated during vertebrate development. Here, we investigated the gene regulatory networks that specify the cholinergic neuronal fates in the spinal cord and forebrain, specifically, spinal motor neurons (MNs) and forebrain cholinergic neurons (FCNs). Conditional inactivation of Isl1, a LIM homeodomain factor expressed in both differentiating MNs and FCNs, led to a drastic loss of cholinergic neurons in the developing spinal cord and forebrain. We found that Isl1 forms two related, but distinct types of complexes, the Isl1-Lhx3-hexamer in MNs and the Isl1-Lhx8-hexamer in FCNs. Interestingly, our genome-wide ChIP-seq analysis revealed that the Isl1-Lhx3-hexamer binds to a suite of cholinergic pathway genes encoding the core constituents of the cholinergic neurotransmission system, such as acetylcholine synthesizing enzymes and transporters. Consistently, the Isl1-Lhx3-hexamer directly coordinated upregulation of cholinergic pathways genes in embryonic spinal cord. Similarly, in the developing forebrain, the Isl1-Lhx8-hexamer was recruited to the cholinergic gene battery and promoted cholinergic gene expression. Furthermore, the expression of the Isl1-Lhx8-complex enabled the acquisition of cholinergic fate in embryonic stem cell-derived neurons. Together, our studies show a shared molecular mechanism that determines the cholinergic neuronal fate in the spinal cord and forebrain, and uncover an important gene regulatory mechanism that directs a specific neurotransmitter identity in vertebrate CNS development.https://doi.org/10.1371/journal.pgen.1004280 |
| spellingShingle | Hyong-Ho Cho Francesca Cargnin Yujin Kim Bora Lee Ryuk-Jun Kwon Heejin Nam Rongkun Shen Anthony P Barnes Jae W Lee Seunghee Lee Soo-Kyung Lee Isl1 directly controls a cholinergic neuronal identity in the developing forebrain and spinal cord by forming cell type-specific complexes. PLoS Genetics |
| title | Isl1 directly controls a cholinergic neuronal identity in the developing forebrain and spinal cord by forming cell type-specific complexes. |
| title_full | Isl1 directly controls a cholinergic neuronal identity in the developing forebrain and spinal cord by forming cell type-specific complexes. |
| title_fullStr | Isl1 directly controls a cholinergic neuronal identity in the developing forebrain and spinal cord by forming cell type-specific complexes. |
| title_full_unstemmed | Isl1 directly controls a cholinergic neuronal identity in the developing forebrain and spinal cord by forming cell type-specific complexes. |
| title_short | Isl1 directly controls a cholinergic neuronal identity in the developing forebrain and spinal cord by forming cell type-specific complexes. |
| title_sort | isl1 directly controls a cholinergic neuronal identity in the developing forebrain and spinal cord by forming cell type specific complexes |
| url | https://doi.org/10.1371/journal.pgen.1004280 |
| work_keys_str_mv | AT hyonghocho isl1directlycontrolsacholinergicneuronalidentityinthedevelopingforebrainandspinalcordbyformingcelltypespecificcomplexes AT francescacargnin isl1directlycontrolsacholinergicneuronalidentityinthedevelopingforebrainandspinalcordbyformingcelltypespecificcomplexes AT yujinkim isl1directlycontrolsacholinergicneuronalidentityinthedevelopingforebrainandspinalcordbyformingcelltypespecificcomplexes AT boralee isl1directlycontrolsacholinergicneuronalidentityinthedevelopingforebrainandspinalcordbyformingcelltypespecificcomplexes AT ryukjunkwon isl1directlycontrolsacholinergicneuronalidentityinthedevelopingforebrainandspinalcordbyformingcelltypespecificcomplexes AT heejinnam isl1directlycontrolsacholinergicneuronalidentityinthedevelopingforebrainandspinalcordbyformingcelltypespecificcomplexes AT rongkunshen isl1directlycontrolsacholinergicneuronalidentityinthedevelopingforebrainandspinalcordbyformingcelltypespecificcomplexes AT anthonypbarnes isl1directlycontrolsacholinergicneuronalidentityinthedevelopingforebrainandspinalcordbyformingcelltypespecificcomplexes AT jaewlee isl1directlycontrolsacholinergicneuronalidentityinthedevelopingforebrainandspinalcordbyformingcelltypespecificcomplexes AT seungheelee isl1directlycontrolsacholinergicneuronalidentityinthedevelopingforebrainandspinalcordbyformingcelltypespecificcomplexes AT sookyunglee isl1directlycontrolsacholinergicneuronalidentityinthedevelopingforebrainandspinalcordbyformingcelltypespecificcomplexes |