Gene expression differences associated with intrinsic hindfoot muscle loss in the jerboa, Jaculus jaculus
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Abstract
Vertebrate animals that run or jump across sparsely vegetated habitats, such as horses and jerboas, have reduced the number of distal limb bones, and many have lost most or all distal limb muscle. We previously showed that nascent muscles are present in the jerboa hindfoot at birth and that these myofibers are rapidly and completely lost soon after by a process that shares features with pathological skeletal muscle atrophy. Here, we apply an intra- and inter-species approach, comparing jerboa and mouse muscles, to identify gene expression differences associated with the initiation and progression of jerboa hindfoot muscle loss. We show evidence for reduced Hepatocyte Growth Factor (HGF) and Fibroblast Growth Factor (FGF) signaling and an imbalance in nitric oxide signaling; all are pathways that are necessary for skeletal muscle development and regeneration. We also find evidence for phagosome formation, which hints at how myofibers may be removed by autophagy or by non-professional phagocytes without evidence for cell death or immune cell activation. Last, we show significant overlap between genes associated with jerboa hindfoot muscle loss and genes that are differentially expressed in a variety of human muscle pathologies and rodent models of muscle loss disorders. All together, these data provide molecular insight into the mechanism of evolutionary and developmental muscle loss in jerboa hindfeet.
Article activity feed
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In this manuscript, the authors use comparative transcriptomics across mouse and gerboa to investigate gene pathways that may be associated with loss of hindfoot muscles in gerboas. The authors generate RNA-seq data from forelimb and hindlimb muscles in mouse and gerboa and perform both inter-specific and intra-specific differential expression analyses to narrow down their list of genes to those that may be particularly associated with the gerboa trait. The authors then cross-reference these data with expression data from human disease contexts, identifying muscle atrophy as a potentially shared feature between developmental muscle loss in gerboas and human muscle phenotypes.
The authors acknowledge that the data presented may be incomplete. Nevertheless, I think this study provides an interesting framework for performing cross-species …
In this manuscript, the authors use comparative transcriptomics across mouse and gerboa to investigate gene pathways that may be associated with loss of hindfoot muscles in gerboas. The authors generate RNA-seq data from forelimb and hindlimb muscles in mouse and gerboa and perform both inter-specific and intra-specific differential expression analyses to narrow down their list of genes to those that may be particularly associated with the gerboa trait. The authors then cross-reference these data with expression data from human disease contexts, identifying muscle atrophy as a potentially shared feature between developmental muscle loss in gerboas and human muscle phenotypes.
The authors acknowledge that the data presented may be incomplete. Nevertheless, I think this study provides an interesting framework for performing cross-species expression analyses. I think future studies including expression data from more species, including members of each lineage that either have or lack the phenotype of interest (hindfoot muscle loss) would help clarify which genes are truly important for this trait, as opposed to simply different across species due to evolutionary changes shared along each lineage that are unrelated to the phenotype of interest. Correcting for fore- and hind-foot differences in intraspecific analyses may not remove those confounding genes, particularly if gene expression is evolving independently in these tissues in each lineage.
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Data Accessibility
Do the authors plan to share the code that underpins these analyses at a future date?
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datasets are likely incomplete and include false positives
It would be interesting in future studies to include transcriptome information from more rodents, to be able to determine what changes in gene expression have occurred along the gerboa lineage which may not be associated with changes in morphology. This would allow for winnowing the list down to fewer candidates.
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Together, these intersections lend support to a hypothesis that jerboa hindfoot muscle loss progresses with a gene expression profile similar to pathological atrophy
Given that the morphology of the jerboa hindfoot is quite different from mouse, how expected would it be that atrophy is responsible for loss of these muscles? Are these muscles under less stress / use within the jerboa physiology as opposed to mouse?
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and at P3
What do the dark grey bars mean in this analysis? They do not seem to be reflected in the color scale.
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Principal components analysis of all jerboa and mouse hindfoot and flexor digitorum superficialis (FDS) transcriptomes.
Slightly decreasing the opacity of each point might make it clearer to see that there are multiple points for each species / stage of development / tissue.
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