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A Hox regulatory network of hindbrain segmentation is conserved to the base of vertebrates.

Parker HJ, Bronner ME, Krumlauf R - Nature (2014)

Bottom Line: Regulatory regions from diverse gnathostomes drive segmental reporter expression in the lamprey hindbrain and require the same transcriptional inputs (for example, Kreisler (also known as Mafba), Krox20 (also known as Egr2a)) in both lamprey and zebrafish.We find that lamprey hox genes display dynamic segmentally restricted domains of expression; we also isolated a conserved exonic hox2 enhancer from lamprey that drives segmental expression in rhombomeres 2 and 4.Our results show that coupling of Hox gene expression to segmentation of the hindbrain is an ancient trait with origin at the base of vertebrates that probably led to the formation of rhombomeric compartments with an underlying Hox code.

View Article: PubMed Central - PubMed

Affiliation: Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA.

ABSTRACT
A defining feature governing head patterning of jawed vertebrates is a highly conserved gene regulatory network that integrates hindbrain segmentation with segmentally restricted domains of Hox gene expression. Although non-vertebrate chordates display nested domains of axial Hox expression, they lack hindbrain segmentation. The sea lamprey, a jawless fish, can provide unique insights into vertebrate origins owing to its phylogenetic position at the base of the vertebrate tree. It has been suggested that lamprey may represent an intermediate state where nested Hox expression has not been coupled to the process of hindbrain segmentation. However, little is known about the regulatory network underlying Hox expression in lamprey or its relationship to hindbrain segmentation. Here, using a novel tool that allows cross-species comparisons of regulatory elements between jawed and jawless vertebrates, we report deep conservation of both upstream regulators and segmental activity of enhancer elements across these distant species. Regulatory regions from diverse gnathostomes drive segmental reporter expression in the lamprey hindbrain and require the same transcriptional inputs (for example, Kreisler (also known as Mafba), Krox20 (also known as Egr2a)) in both lamprey and zebrafish. We find that lamprey hox genes display dynamic segmentally restricted domains of expression; we also isolated a conserved exonic hox2 enhancer from lamprey that drives segmental expression in rhombomeres 2 and 4. Our results show that coupling of Hox gene expression to segmentation of the hindbrain is an ancient trait with origin at the base of vertebrates that probably led to the formation of rhombomeric compartments with an underlying Hox code.

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Developmental time-course of GFP reporter expression mediated by lamprey and gnathostome regulatory elements in lamprey embryosStages 18 to 26 are shown. All embryos are positioned such that the hindbrain is viewed dorsally, with anterior to the top, except for Hoxb4(m) at stage 22, which is viewed laterally with anterior to the left. Black boxes indicate no GFP expression mediated by that element at that developmental stage. In both fish and lamprey, expression driven by the gnathostome Hoxb1 enhancers appear to be temporally dynamic, starting broad and refining with time, likely caused by autoregulation within this element. However, we cannot rule out the possibility that the enhancers used may be missing some repressor elements that are required for fine-tuning.
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Figure 8: Developmental time-course of GFP reporter expression mediated by lamprey and gnathostome regulatory elements in lamprey embryosStages 18 to 26 are shown. All embryos are positioned such that the hindbrain is viewed dorsally, with anterior to the top, except for Hoxb4(m) at stage 22, which is viewed laterally with anterior to the left. Black boxes indicate no GFP expression mediated by that element at that developmental stage. In both fish and lamprey, expression driven by the gnathostome Hoxb1 enhancers appear to be temporally dynamic, starting broad and refining with time, likely caused by autoregulation within this element. However, we cannot rule out the possibility that the enhancers used may be missing some repressor elements that are required for fine-tuning.

Mentions: When tested for regulatory activity in lamprey, the same gnathostome constructs mediated segmental reporter expression reminiscent of that seen in their host species and/or zebrafish. The restricted stripes of GFP expression reflect an ordered series of domains (Fig.1b, Extended Data Fig.2 & Table2), implying that these gnathostome enhancers are activated by upstream lamprey factors to mediate reporter expression in a rhombomeric fashion. Reporter expression spans multiple developmental stages (st) with variable onset between elements (Extended Data Fig.4). The Hoxb1 enhancer is active first (st18) in a broad domain that becomes restricted over time, followed by Hoxb2 (st21), Hoxb3 and Hoxb4 (st22). These data suggest that a similar underlying hindbrain GRN, with temporal colinearity reminiscent of gnathostomes, may be present in lamprey.


A Hox regulatory network of hindbrain segmentation is conserved to the base of vertebrates.

Parker HJ, Bronner ME, Krumlauf R - Nature (2014)

Developmental time-course of GFP reporter expression mediated by lamprey and gnathostome regulatory elements in lamprey embryosStages 18 to 26 are shown. All embryos are positioned such that the hindbrain is viewed dorsally, with anterior to the top, except for Hoxb4(m) at stage 22, which is viewed laterally with anterior to the left. Black boxes indicate no GFP expression mediated by that element at that developmental stage. In both fish and lamprey, expression driven by the gnathostome Hoxb1 enhancers appear to be temporally dynamic, starting broad and refining with time, likely caused by autoregulation within this element. However, we cannot rule out the possibility that the enhancers used may be missing some repressor elements that are required for fine-tuning.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4209185&req=5

Figure 8: Developmental time-course of GFP reporter expression mediated by lamprey and gnathostome regulatory elements in lamprey embryosStages 18 to 26 are shown. All embryos are positioned such that the hindbrain is viewed dorsally, with anterior to the top, except for Hoxb4(m) at stage 22, which is viewed laterally with anterior to the left. Black boxes indicate no GFP expression mediated by that element at that developmental stage. In both fish and lamprey, expression driven by the gnathostome Hoxb1 enhancers appear to be temporally dynamic, starting broad and refining with time, likely caused by autoregulation within this element. However, we cannot rule out the possibility that the enhancers used may be missing some repressor elements that are required for fine-tuning.
Mentions: When tested for regulatory activity in lamprey, the same gnathostome constructs mediated segmental reporter expression reminiscent of that seen in their host species and/or zebrafish. The restricted stripes of GFP expression reflect an ordered series of domains (Fig.1b, Extended Data Fig.2 & Table2), implying that these gnathostome enhancers are activated by upstream lamprey factors to mediate reporter expression in a rhombomeric fashion. Reporter expression spans multiple developmental stages (st) with variable onset between elements (Extended Data Fig.4). The Hoxb1 enhancer is active first (st18) in a broad domain that becomes restricted over time, followed by Hoxb2 (st21), Hoxb3 and Hoxb4 (st22). These data suggest that a similar underlying hindbrain GRN, with temporal colinearity reminiscent of gnathostomes, may be present in lamprey.

Bottom Line: Regulatory regions from diverse gnathostomes drive segmental reporter expression in the lamprey hindbrain and require the same transcriptional inputs (for example, Kreisler (also known as Mafba), Krox20 (also known as Egr2a)) in both lamprey and zebrafish.We find that lamprey hox genes display dynamic segmentally restricted domains of expression; we also isolated a conserved exonic hox2 enhancer from lamprey that drives segmental expression in rhombomeres 2 and 4.Our results show that coupling of Hox gene expression to segmentation of the hindbrain is an ancient trait with origin at the base of vertebrates that probably led to the formation of rhombomeric compartments with an underlying Hox code.

View Article: PubMed Central - PubMed

Affiliation: Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA.

ABSTRACT
A defining feature governing head patterning of jawed vertebrates is a highly conserved gene regulatory network that integrates hindbrain segmentation with segmentally restricted domains of Hox gene expression. Although non-vertebrate chordates display nested domains of axial Hox expression, they lack hindbrain segmentation. The sea lamprey, a jawless fish, can provide unique insights into vertebrate origins owing to its phylogenetic position at the base of the vertebrate tree. It has been suggested that lamprey may represent an intermediate state where nested Hox expression has not been coupled to the process of hindbrain segmentation. However, little is known about the regulatory network underlying Hox expression in lamprey or its relationship to hindbrain segmentation. Here, using a novel tool that allows cross-species comparisons of regulatory elements between jawed and jawless vertebrates, we report deep conservation of both upstream regulators and segmental activity of enhancer elements across these distant species. Regulatory regions from diverse gnathostomes drive segmental reporter expression in the lamprey hindbrain and require the same transcriptional inputs (for example, Kreisler (also known as Mafba), Krox20 (also known as Egr2a)) in both lamprey and zebrafish. We find that lamprey hox genes display dynamic segmentally restricted domains of expression; we also isolated a conserved exonic hox2 enhancer from lamprey that drives segmental expression in rhombomeres 2 and 4. Our results show that coupling of Hox gene expression to segmentation of the hindbrain is an ancient trait with origin at the base of vertebrates that probably led to the formation of rhombomeric compartments with an underlying Hox code.

Show MeSH