Abstract
Vertebrate appendage regeneration requires precisely coordinated remodeling of the transcriptional landscape to enable the growth and differentiation of new tissue, a process executed over multiple days and across dozens of cell types. The heterogeneity of tissues and temporally-sensitive fate decisions involved has made it difficult to articulate the gene regulatory programs enabling regeneration of individual cell types. To better understand how a regenerative program is fulfilled by neural progenitor cells (NPCs) of the spinal cord, we analyzed pax6-expressing NPCs isolated from regenerating Xenopus tropicalis tails. By intersecting chromatin accessibility data with single-cell transcriptomics, we find that NPCs place an early priority on neuronal differentiation. Late in regeneration, the priority returns to proliferation. Our analyses identify Pbx3 and Meis1 as critical regulators of tail regeneration and axon organization. Overall, we use transcriptional regulatory dynamics to present a new model for cell fate decisions and their regulators in NPCs during regeneration.
Highlights
Humans have long been fascinated by regeneration and the elegance it presents as a treatment for traumatic injury
Using neural progenitor cells with the Xtr.Tg(pax6:GFP;cryga:RFP;actc1:RFP)Papal (Hartley et al, 2001; Hirsch et al, 2002) transgenic line as a test case, we evaluated the quality of RNA or chromatin extracted from cells that have gone through the sorting process by comparing gene expression and chromatin accessibility to cells that were not sorted
If we look at regions more accessible in the pax6 libraries called in the gene ontology (GO) term “Nervous system development”, we see that known neural markers are more accessible (Figure 2-5C), indicating that purifying cells from a transgenic reporter by fluorescence activated cell sorting (FACS) presents a method to increase the resolution of bulk ATAC-Seq for a cell type of interest
Summary
Humans have long been fascinated by regeneration and the elegance it presents as a treatment for traumatic injury. The story of Prometheus captures the fact that humans can regenerate their livers (albeit in an extreme way), regenerative capacity in other tissues is quite restricted (Koniaris et al, 2003) With this knowledge, we find ourselves in admiration of contemporary characters like Wolverine, who has a seemingly limitless regenerative capacity, being able to regenerate heavily injured tissues by the use of his healing factor. Genome-wide transcriptomic studies have confirmed that numerous genes associated with embryonic development are reexpressed during regeneration (Chang et al, 2017b; Lee-Liu et al, 2014b; Love et al, 2011) These studies have been carried out on bulk regenerating tissue, making it difficult to identify what signals or factors are required to promote regeneration in specific cell types
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