Early molecular events during retinoic acid induced differentiation of neuromesodermal progenitors
Bipotent neuromesodermal progenitors (NMPs) residing in the caudal epiblast drive coordinated body axis extension by generating both posterior neuroectoderm and presomitic mesoderm. Retinoic acid (RA) is required for body axis extension, however the early molecular response to RA signaling is poorly...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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The Company of Biologists
2016-12-01
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| Series: | Biology Open |
| Subjects: | |
| Online Access: | http://bio.biologists.org/content/5/12/1821 |
| _version_ | 1830485610247225344 |
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| author | Thomas J. Cunningham Alexandre Colas Gregg Duester |
| author_facet | Thomas J. Cunningham Alexandre Colas Gregg Duester |
| author_sort | Thomas J. Cunningham |
| collection | DOAJ |
| description | Bipotent neuromesodermal progenitors (NMPs) residing in the caudal epiblast drive coordinated body axis extension by generating both posterior neuroectoderm and presomitic mesoderm. Retinoic acid (RA) is required for body axis extension, however the early molecular response to RA signaling is poorly defined, as is its relationship to NMP biology. As endogenous RA is first seen near the time when NMPs appear, we used WNT/FGF agonists to differentiate embryonic stem cells to NMPs which were then treated with a short 2-h pulse of 25 nM RA or 1 µM RA followed by RNA-seq transcriptome analysis. Differential expression analysis of this dataset indicated that treatment with 25 nM RA, but not 1 µM RA, provided physiologically relevant findings. The 25 nM RA dataset yielded a cohort of previously known caudal RA target genes including Fgf8 (repressed) and Sox2 (activated), plus novel early RA signaling targets with nearby conserved RA response elements. Importantly, validation of top-ranked genes in vivo using RA-deficient Raldh2−/− embryos identified novel examples of RA activation (Nkx1-2, Zfp503, Zfp703, Gbx2, Fgf15, Nt5e) or RA repression (Id1) of genes expressed in the NMP niche or progeny. These findings provide evidence for early instructive and permissive roles of RA in controlling differentiation of NMPs to neural and mesodermal lineages. |
| first_indexed | 2024-12-21T18:27:23Z |
| format | Article |
| id | doaj.art-5d801cae95ba43a88a08c5394f6b1603 |
| institution | Directory Open Access Journal |
| issn | 2046-6390 |
| language | English |
| last_indexed | 2024-12-21T18:27:23Z |
| publishDate | 2016-12-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Biology Open |
| spelling | doaj.art-5d801cae95ba43a88a08c5394f6b16032022-12-21T18:54:22ZengThe Company of BiologistsBiology Open2046-63902016-12-015121821183310.1242/bio.020891020891Early molecular events during retinoic acid induced differentiation of neuromesodermal progenitorsThomas J. Cunningham0Alexandre Colas1Gregg Duester2 Development, Aging, and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA Development, Aging, and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA Development, Aging, and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA Bipotent neuromesodermal progenitors (NMPs) residing in the caudal epiblast drive coordinated body axis extension by generating both posterior neuroectoderm and presomitic mesoderm. Retinoic acid (RA) is required for body axis extension, however the early molecular response to RA signaling is poorly defined, as is its relationship to NMP biology. As endogenous RA is first seen near the time when NMPs appear, we used WNT/FGF agonists to differentiate embryonic stem cells to NMPs which were then treated with a short 2-h pulse of 25 nM RA or 1 µM RA followed by RNA-seq transcriptome analysis. Differential expression analysis of this dataset indicated that treatment with 25 nM RA, but not 1 µM RA, provided physiologically relevant findings. The 25 nM RA dataset yielded a cohort of previously known caudal RA target genes including Fgf8 (repressed) and Sox2 (activated), plus novel early RA signaling targets with nearby conserved RA response elements. Importantly, validation of top-ranked genes in vivo using RA-deficient Raldh2−/− embryos identified novel examples of RA activation (Nkx1-2, Zfp503, Zfp703, Gbx2, Fgf15, Nt5e) or RA repression (Id1) of genes expressed in the NMP niche or progeny. These findings provide evidence for early instructive and permissive roles of RA in controlling differentiation of NMPs to neural and mesodermal lineages.http://bio.biologists.org/content/5/12/1821Embryonic stem cellsNeuromesodermal progenitorsRaldh2 knockout embryosRetinoic acid target genesNkx1-2Zfp503Zfp703Gbx2Id1Retinoic acid response elements |
| spellingShingle | Thomas J. Cunningham Alexandre Colas Gregg Duester Early molecular events during retinoic acid induced differentiation of neuromesodermal progenitors Biology Open Embryonic stem cells Neuromesodermal progenitors Raldh2 knockout embryos Retinoic acid target genes Nkx1-2 Zfp503 Zfp703 Gbx2 Id1 Retinoic acid response elements |
| title | Early molecular events during retinoic acid induced differentiation of neuromesodermal progenitors |
| title_full | Early molecular events during retinoic acid induced differentiation of neuromesodermal progenitors |
| title_fullStr | Early molecular events during retinoic acid induced differentiation of neuromesodermal progenitors |
| title_full_unstemmed | Early molecular events during retinoic acid induced differentiation of neuromesodermal progenitors |
| title_short | Early molecular events during retinoic acid induced differentiation of neuromesodermal progenitors |
| title_sort | early molecular events during retinoic acid induced differentiation of neuromesodermal progenitors |
| topic | Embryonic stem cells Neuromesodermal progenitors Raldh2 knockout embryos Retinoic acid target genes Nkx1-2 Zfp503 Zfp703 Gbx2 Id1 Retinoic acid response elements |
| url | http://bio.biologists.org/content/5/12/1821 |
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