Hedgehog Signaling during Appendage Development  and Regeneration

Singh, Bhairab N.; Koyano-Nakagawa, Naoko; Donaldson, Andrew; Weaver, Cyprian; Garry, Mary G.; Garry, Daniel J.

doi:10.3390/genes6020417

Cited by 29 publications

(30 citation statements)

References 97 publications

(252 reference statements)

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“…Therefore, our findings suggest that repression of these pathways in early stages of regeneration may be necessary and that precise timely release of inhibition ensures successful regeneration. It is interesting to note that the analysis did not reveal strong predictions for activation or repression of other pathways essential for limb regeneration, such as sonic hedgehog (shh) signaling (Singh et al, 2015). These other pathways may be downstream and act at later stages of regeneration (or are regulated post-transcriptionally).…”

Section: Discussionmentioning

confidence: 99%

Blastemal progenitors modulate immune signaling during early limb regeneration

2019

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Blastema formation, a hallmark of limb regeneration, requires proliferation and migration of progenitors to the amputation plane. Although blastema formation has been well described, the transcriptional programs that drive blastemal progenitors remain unknown. We transcriptionally profiled dividing and non-dividing cells in regenerating stump tissues, as well as the wound epidermis, during early axolotl limb regeneration. Our analysis revealed unique transcriptional signatures of early dividing cells and, unexpectedly, repression of several core developmental signaling pathways in early regenerating stump tissues. We further identify an immunomodulatory role for blastemal progenitors through interleukin 8 (IL-8), a highly expressed cytokine in subpopulations of early blastemal progenitors. Ectopic il-8 expression in nonregenerating limbs induced myeloid cell recruitment, while IL-8 knockdown resulted in defective myeloid cell retention during late wound healing, delaying regeneration. Furthermore, the il-8 receptor cxcr-1/2 was expressed in myeloid cells, and inhibition of CXCR-1/2 signaling during early stages of limb regeneration prevented regeneration. Altogether, our findings suggest that blastemal progenitors are active early mediators of immune support, and identify CXCR-1/2 signaling as an important immunomodulatory pathway during the initiation of regeneration.

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Section: Discussionmentioning

confidence: 99%

Blastemal progenitors modulate immune signaling during early limb regeneration

2019

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“…In lower vertebrates, differentiated cells can revert to a fetal-like stage with high proliferative capacity to repair damaged tissue. Thereafter, redifferentiation into the adult cell types allows restoration of full tissue functionality ( Singh et al, 2015 ). Lineage-tracing approaches in the mouse have revealed that a similar process of de-differentiation can occur during epithelium repair in mammals.…”

Section: Discussionmentioning

confidence: 99%

Trop2 marks transient gastric fetal epithelium and adult regenerating cells after epithelial damage

et al. 2016

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Mouse fetal intestinal progenitors lining the epithelium prior to villogenesis grow as spheroids when cultured ex vivo and express the transmembrane glycoprotein Trop2 as a marker. Here, we report the characterization of Trop2-expressing cells from fetal pre-glandular stomach, growing as immortal undifferentiated spheroids, and their relationship with gastric development and regeneration. Trop2+ cells generating gastric spheroids differed from adult glandular Lgr5+ stem cells, but appeared highly related to fetal intestinal spheroids. Although they shared a common spheroid signature, intestinal and gastric fetal spheroid-generating cells expressed organ-specific transcription factors and were committed to intestinal and glandular gastric differentiation, respectively. Trop2 expression was transient during glandular stomach development, being lost at the onset of gland formation, whereas it persisted in the squamous forestomach. Undetectable under homeostasis, Trop2 was strongly re-expressed in glands after acute Lgr5+ stem cell ablation or following indomethacin-induced injury. These highly proliferative reactive adult Trop2+ cells exhibited a transcriptome displaying similarity with that of gastric embryonic Trop2+ cells, suggesting that epithelium regeneration in adult stomach glands involves the partial re-expression of a fetal genetic program.

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“…These observations suggest that precocious progenitor differentiation, potentially as a result of abrogated Hh signaling, may be a significant mechanism underlying CHD. Hosoya et al, 2020;Ingham and Placzek, 2006;Ingham et al, 2011;Jiang and Hui, 2008;Lee et al, 2016;McMahon et al, 2003;Singh et al, 2015;Wallace, 2008). Global disruption of Hh signaling during embryogenesis causes pleiotropic developmental syndromes, including VACTERL syndrome, Gorlin Syndrome, holoprosencephaly and Greig cephalopolysyndactyly syndrome (Hui and Angers, 2011;McMahon et al, 2003;Ngan et al, 2012;Nieuwenhuis and Hui, 2005).…”

Section: Foxf1 Directly Represses a Cardiomyocyte Differentiation Promentioning

confidence: 99%

Hedgehog signaling activates a heterochronic gene regulatory network to control differentiation timing across lineages

Rowton

Perez-Cervantes

Rydeen

et al. 2018

Preprint

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Hedgehog (Hh) signaling acts as a developmental morphogen that contributes to the diversification of cell fates and tissue patterning in multiple embryonic contexts, as well as regulating the proliferation of adult tissue stem cells1-9. Here, we report a novel function of Hh signaling GLI transcription factors (TFs) in directly governing the timing of cellular differentiation, independent of a role in specification or proliferation. Disruption of active Hh signaling in the embryo resulted in reduced expression of a progenitor-specific transcription factor network and the inappropriate activation of cardiac differentiation-specific gene expression programs. Expression of the activating Hh transcription factor, GLI1, a marker and effector of active Hh signaling, is correlated with stem and progenitor states during the differentiation of all three germ layers in mouse and human. Transient induction of GLI1 in mouse embryonic stem cell (mESC)-derived cardiac and neural progenitors delayed the onset of the cardiomyocyte and neuron differentiation programs, respectively, while activating progenitor-specific gene expression. GLI1 expression in cardiac progenitors promoted a shift in chromatin accessibility towards a progenitor-like profile at distal regulatory elements near Hh-dependent genes. Manipulating the balance of active to repressive GLI TF predominance unveiled a molecular switch that determined the activity patterns of progenitor-specific distal cis-regulatory elements in vitro and in vivo. Overriding this switch through forced expression of a repressive GLI TF in cardiac progenitors in vivo caused precocious cardiomyocyte differentiation and Congenital Heart Disease (CHD). Our data suggest that a GLI TF switch at distal regulatory elements maintains progenitor cell status and inhibits premature differentiation through the activation and maintenance of a progenitor-specific regulatory network, thus controlling progenitor differentiation timing. We propose a novel molecular paradigm for progenitor maintenance in diverse cellular contexts by signal-dependent TFs with implications for organ development, regenerative potential, and Hh-driven cancers.

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Hedgehog Signaling during Appendage Development and Regeneration

Cited by 29 publications

References 97 publications

Blastemal progenitors modulate immune signaling during early limb regeneration

Blastemal progenitors modulate immune signaling during early limb regeneration

Trop2 marks transient gastric fetal epithelium and adult regenerating cells after epithelial damage

Hedgehog signaling activates a heterochronic gene regulatory network to control differentiation timing across lineages

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