Nr6a1 controls Hox expression dynamics and is a master regulator of vertebrate trunk development
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA748234 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15096320.fastq.gz | Fastqsanger.gz | |||
| SRR15096321.fastq.gz | Fastqsanger.gz | |||
| SRR15096322.fastq.gz | Fastqsanger.gz | |||
| SRR15096323.fastq.gz | Fastqsanger.gz | |||
| SRR15096324.fastq.gz | Fastqsanger.gz |
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Project description:The vertebrate main-body axis is laid down during embryonic stages in an anterior-to-posterior (head-to-tail) direction, driven and supplied by posteriorly located progenitors. Whilst posterior expansion and segmentation appears broadly uniform along the axis, there is developmental and evolutionary support for at least two discrete modules controlling processes within different axial regions: a trunk and a tail module. Here, we identify Nuclear receptor subfamily 6 group A member 1 (Nr6a1) as a master regulator of trunk development in the mouse. Specifically, Nr6a1 was found to control vertebral number and segmentation of the trunk region, autonomously from other axial regions. Moreover, Nr6a1 was essential for the timely progression of Hox signatures, and neural versus mesodermal cell fate choice, within axial progenitors. Collectively, Nr6a1 has an axially-restricted role in all major cellular and tissue-level events required for vertebral column formation, supporting the view that changes in Nr6a1 levels may underlie evolutionary changes in axial formulae.
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Project description:The vertebrate main-body axis is laid down during embryonic stages in an anterior-to-posterior (head-to-tail) direction, driven and supplied by posteriorly located progenitors. For the vertebral column, the process of axial progenitor cell expansion that drives axis elongation, and the process of segmentation which allocates these progenitors into repeating vertebral units, occurs seemingly uninterrupted from the first to the last vertebra. Nonetheless, there is clear developmental and evolutionary support for two discrete modules controlling processes within different axial regions: a trunk module and a tail module. The secreted signal Gdf11 has been identified as a principal regulator of timing the trunk-to-tail (T-to-T) transition, but has pleiotropic effects across much of the main body axis, highlighting the need to reveal intrinsic regulatory networks that function to exclusively control one or the other module. Here, we identify Nuclear receptor subfamily 6 group A member 1 (Nr6a1) as a master regulator of elongation, patterning and lineage allocation specifically within the trunk region of the mouse. Both gain- and loss-of-function in vivo analysis revealed that the precise level of Nr6a1 acts as a rheostat, expanding or contracting vertebral number of the trunk region autonomously from other axial regions. Moreover, the timely clearance of Nr6a1 observed at the T-to-T transition was essential in allowing the tail module to operate correctly. In parallel with these effects on vertebral number, we show that Nr6a1 controls the timely progression of global Hox signatures within axial progenitors, preventing the precocious expression of multiple posterior Hox genes as the trunk is being laid down and thus reinforcing that patterning and elongation are coordinated. Finally, our data supports a crucial role for Nr6a1 in regulating gene regulatory networks that guide cell lineage choice of axial progenitors between neural and mesodermal fate. Collectively, our data reveals an axially-restricted role for Nr6a1 in all major cellular and tissue-level events required for vertebral column formation, supporting the view that modulation of Nr6a1 expression level or function may underpin evolutionary changes in axial formulae that exclusively alter the trunk region.
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Project description:The vertebrate main-body axis is laid down during embryonic stages in an anterior-to-posterior (head-to-tail) direction, driven and supplied by posteriorly located progenitors. For the vertebral column, the process of axial progenitor cell expansion that drives axis elongation, and the process of segmentation which allocates these progenitors into repeating vertebral units, occurs seemingly uninterrupted from the first to the last vertebra. Nonetheless, there is clear developmental and evolutionary support for two discrete modules controlling processes within different axial regions: a trunk module and a tail module. The secreted signal Gdf11 has been identified as a principal regulator of timing the trunk-to-tail (T-to-T) transition, but has pleiotropic effects across much of the main body axis, highlighting the need to reveal intrinsic regulatory networks that function to exclusively control one or the other module. Here, we identify Nuclear receptor subfamily 6 group A member 1 (Nr6a1) as a master regulator of elongation, patterning and lineage allocation specifically within the trunk region of the mouse. Both gain- and loss-of-function in vivo analysis revealed that the precise level of Nr6a1 acts as a rheostat, expanding or contracting vertebral number of the trunk region autonomously from other axial regions. Moreover, the timely clearance of Nr6a1 observed at the T-to-T transition was essential in allowing the tail module to operate correctly. In parallel with these effects on vertebral number, we show that Nr6a1 controls the timely progression of global Hox signatures within axial progenitors, preventing the precocious expression of multiple posterior Hox genes as the trunk is being laid down and thus reinforcing that patterning and elongation are coordinated. Finally, our data supports a crucial role for Nr6a1 in regulating gene regulatory networks that guide cell lineage choice of axial progenitors between neural and mesodermal fate. Collectively, our data reveals an axially-restricted role for Nr6a1 in all major cellular and tissue-level events required for vertebral column formation, supporting the view that modulation of Nr6a1 expression level or function may underpin evolutionary changes in axial formulae that exclusively alter the trunk region.
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Project description:The formation of the vertebrate body is driven by the progressive and coordinated production of trunk tissues from pools of progenitors located in the posterior of the embryo. Aspects of this process are recapitulated by in vitro models based on pluripotent stem cells (PSCs). However, these models lack several tissue components normally found in the vertebrate trunk. Most strikingly, the notochord, a hallmark of chordates and the source of midline signals that pattern surrounding tissues, is absent from current models of human trunk formation. To investigate how trunk tissue is formed, we performed single-cell transcriptomic analysis of chick embryos. This delineated molecularly discrete progenitor populations, which we spatially locate in the embryo and relate to signalling activity. Guided by this map, we determined how a stereotypical spatial organization of tissue types arises in differentiating human PSCs. This involved LATS1/2 mediated repression of YAP activity facilitating WNT signalling, that, together with FGF mediated ERK1/2 activation, induces the transcription factor Bra/TBXT. In addition, timely inhibition of a WNT-induced NODAL and BMP signalling cascade regulates the proportions of different tissue types produced, including notochordal cells. We exploit this to develop an integrated 3D model of human notochord and neural tissue formation. Together the data provide insight into the mechanisms responsible for the formation of the tissues that comprise the vertebrate trunk and pave the way for future studies of patterning in a tissue-like environment.
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Project description:The formation of the vertebrate body is driven by the progressive and coordinated production of trunk tissues from pools of progenitors located in the posterior of the embryo. Aspects of this process are recapitulated by in vitro models based on pluripotent stem cells (PSCs). However, these models lack several tissue components normally found in the vertebrate trunk. Most strikingly, the notochord, a hallmark of chordates and the source of midline signals that pattern surrounding tissues, is absent from current models of human trunk formation. To investigate how trunk tissue is formed, we performed single-cell transcriptomic analysis of chick embryos. This delineated molecularly discrete progenitor populations, which we spatially locate in the embryo and relate to signalling activity. Guided by this map, we determined how a stereotypical spatial organization of tissue types arises in differentiating human PSCs. This involved LATS1/2 mediated repression of YAP activity facilitating WNT signalling, that, together with FGF mediated ERK1/2 activation, induces the transcription factor Bra/TBXT. In addition, timely inhibition of a WNT-induced NODAL and BMP signalling cascade regulates the proportions of different tissue types produced, including notochordal cells. We exploit this to develop an integrated 3D model of human notochord and neural tissue formation. Together the data provide insight into the mechanisms responsible for the formation of the tissues that comprise the vertebrate trunk and pave the way for future studies of patterning in a tissue-like environment.
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