Combinatorial interactions of Hox genes establish appendage diversity of the amphipod crustacean Parhyale hawaiensis
Posted on: 14 April 2022
Preprint posted on 27 March 2022
Distinct regulation of Hox genes by Polycomb Group genes in a crustacean
Posted on:
Preprint posted on 28 March 2022
Categories: developmental biology, evolutionary biology, genetics
Background
Hox genes act as master regulators of anterior-to-posterior (AP) axial identity in nearly all animals. Precise spatial and temporal regulation of these genes during embryogenesis is crucial for establishing a normal body plan. The regulation of Hox genes is tightly linked to their genomic organisation; they tend to be clustered in the genome, and the order of Hox genes in a cluster mirrors their order of expression along the AP axis (a phenomenon known as “spatial collinearity”). .
Hox gene regulation has perhaps been best characterised in the animal in which Hox genes were first discovered, Drosophila. In Drosophila, Hox gene expression boundaries are initially established by genes of the segmentation cascade. They are then reinforced and maintained by Polycomb group (PcG) and Trithorax group (TrxG) genes, which introduce and maintain chromatin modifications, and by cross-regulation between Hox genes. Whether these phases of regulation are representative of the arthropods in general, or are specific to some insects (including Drosophila), remains unclear.
The two preprints I have chosen to highlight here reveal aspects of Hox gene regulation in a non-insect arthropod, the amphipod crustacean Parhyale hawaiensis. Like other crustaceans, Parhyale sports one pair of appendages per segment – this makes it quick and easy to spot homeotic phenotypes using appendage morphology as a readout. The first preprint, by Alberstat et al., focuses on cross-regulation between Hox genes, while the second preprint by Sun et al. focuses on the regulation of Hox genes by PcG and TrxG chromatin modifying enzymes. Both preprints hail from Nipam Patel’s lab, and use a combination of CRISPR/Cas9 mutagenesis and in situ hybridisation to infer regulatory interactions.
Key Findings
Preprint 1 – Posterior prevalence and the Hox code
The first preprint, by Alberstat et al., focuses primarily on cross-regulation of the posterior Hox genes, Ultrabithorax (Ubx), abdominal-A (abd-A) and Abdominal-B (Abd-B). These genes are encoded and expressed at the posterior of the Hox cluster and embryo, respectively. In Drosophila, these genes display a property known as posterior prevalence; posterior genes are phenotypically dominant to more anterior genes. This dominance can emerge through transcriptional or post-transcriptional suppression. By knocking down each of the posterior Hox genes individually and in combination with each other, Alberstat et al. revealed that the situation in Paryhale is a little more complex.
Some Parhyale Hox genes do interact in a manner consistent with the posterior prevalence model. The authors found that Ubx is transcriptionally repressed by the most posterior gene of the cluster, Abd-B, and that Ubx is functionally repressed by its posterior neighbour, abd-A, although this is repression is not at the transcriptional or translational level. They also showed that Ubx, abd-A and Abd-B are all capable of repressing the more anterior Hox gene Sex combs reduced (Scr). However, abd-A does not appear to be repressed transcriptionally or otherwise by any of the other posterior Hox genes. In fact, it is co-expressed with its posterior neighbour, Abd-B, in the swimming appendages, where the two genes act co-operatively to specify appendage identity. Furthermore, abd-A seems to have a dose-dependent effect on appendage identity, with different levels of expression generating different appendage types.
In summary, cross-regulation between Hox genes appears to be essential for normal axial patterning in Parhyale, but does not entirely align with a simple posterior prevalence model. The authors suggest that Parhyale utilises a “Hox code” to pattern its appendages, wherein both the dosage and combination of Hox genes present determine appendage fate. If conserved more broadly amongst the crustaceans, this model might help to explain the huge diversity of appendage types in this lineage.
Figure 1. The combinations and dosages of Hox genes proposed to code for each appendage type in Parhyale. Adapted from Figure 9B in the preprint by Alberstat et al.
Preprint 2 – Polycomb in Parhyale
In the second preprint, by Sun et al., the authors focus on the role of Polycomb Group (PcG) and Trithorax Group (TrxG) genes in regulating Parhyale Hox genes. They found that the genome of Parhyale contains homologs of all core PcG and TrxG genes known in Drosophila. As observed in other animals, knocking out PcG genes generated homeotic transformations and misexpression of Hox genes. They also observed a number of non-homeotic defects in limb patterning, cuticle deposition, and plate formation, suggesting that PcG genes play pleiotropic roles in Parhyale development. Surprisingly, TrxG knockouts did not display any homeotic transformations. It may be that TrxG genes play a more subtle role in regulating Hox gene expression in Parhyale than in Drosophila.
Sun et al. also demonstrate that the interactions between individual PcG and Hox genes are highly gene- and tissue-dependent in Parhyale. Knocking out different PcG genes resulted in different degrees of de-repression for different Hox genes, in a tissue-specific manner. For example, the PcG gene Sce seems to repress Ubx strongly in the nervous system and appendages; abd-A weakly in the nervous system, but not appendages; and Abd-B strongly in the nervous system and very weakly in the appendages. The timing of de-repression also varies between Hox genes – for example, Ubx is initially expressed normally in PcG knockouts, and only subsequently becomes ectopically expressed, while ectopic expression of Abd-B is observed at the same time as the wild-type domain is established.
In summary, Sun et al. show that PcG, but not necessarily TrxG, genes are required for Hox regulation in Parhyale. However, the interactions between PcG and Hox genes are not one-size fits all, and depend on the individual PcG gene and Hox gene in question, and the tissue where they are expressed.
Why I think these two preprints are important
Our understanding of Hox gene regulation is dominated by research from a very small number of model organisms – in particular, Drosophila and mice. By developing detailed models of Hox gene regulation in other organisms, we can make inferences about how it has evolved over time and how this influences axial patterning.
Based on these preprints, it seems likely that the three broad phases of Hox gene regulation identified in Drosophila – PcG-independent anterior boundary establishment, PcG-dependent boundary maintenance, and Hox cross regulation – are conserved in Parhyale, and were a common feature of the ancestor of insects and crustaceans. However, both preprints highlight complexities in regulation that might help Parhyale to fine tune its Hox gene expression and generate its diverse complement of appendages.
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