Biology subjects

Savage, A. M.

Publications and source records attributed to Savage, A. M..

5 recordsLinked to original sources

bioRxiv2025

Pancreatic injury induces β-cell regeneration in axolotl

BackgroundDiabetes is a condition characterized by a loss of pancreatic {beta}-cell function which results in the dysregulation of insulin homeostasis. Using a partial pancreatectomy model in axolotl, we aimed to observe the pancreatic response to injury. ResultsHere we show a comprehensive histological assessment of pancreatic islets in axolotl. Following pancreatic injury, no apparent blastemal structure was observed. We found a significant, organ-wide increase in cellular proliferation post-resection in the pancreas compared to sham-operated controls. This proliferative response was most robust at the site of injury. We found that {beta}-cells actively contributed to the increased rates of proliferation upon injury. {beta}-cell proliferation manifested in increased {beta}-cell mass in injured tissue at two weeks post injury. At four weeks post injury, we found organ-wide proliferation to be extinguished while proliferation at the injury site persisted, corresponding to pancreatic tissue recovery. Similarly, total {beta}-cell mass was comparable to sham after four weeks. ConclusionsOur findings suggest a non-blastema-mediated regeneration process takes place in the pancreas, by which pancreatic resection induces whole-organ {beta}-cell proliferation without the formation of a blastemal structure. This process is analogous to other models of compensatory growth in axolotl, including liver regeneration.

developmental biology↗

bioRxiv2024

An evolutionarily conserved role for VEGF signaling in the expansion of non-vascular tissue during regeneration.

Salamanders are capable of regenerating whole limbs throughout life, a feat that is unmatched within tetrapods. Limb regeneration is dependent upon the formation of a blastema, which contains undifferentiated cells capable of giving rise to most cells of the regenerated limb. Innervation is required for regeneration, along with many signaling pathways, including FGF, BMP and Wnt, but the role of VEGF signaling during salamander limb regeneration is not well understood. Here we show that VEGF signaling is essential for limb regeneration and that blastema cells and limb fibroblasts display impaired proliferation in the absence of VEGF signaling. By performing analogous experiments in planaria, which lack vasculature, we show a potential evolutionarily conserved role for VEGF in the expansion of blastema tissues that is separable from angiogenesis. Moreover, loss of VEGF signaling reduces induction of EMT-like processes, suggesting VEGF signaling functions upstream of the expression of EMT transcription factors, including Snai2. These findings highlight potential roles for VEGF signaling during regeneration which may extend beyond typical findings related to angiogenesis.

developmental biology↗

bioRxiv2024

Amputation Triggers Long-Range Epidermal Permeability Changes in Evolutionarily Distant Regenerative Organisms

Previous studies have reported that amputation invokes body-wide responses in regenerative organisms, but most have not examined the implications of these changes beyond the region of tissue regrowth. Specifically, long-range epidermal responses to amputation are largely uncharacterized, with research on amputation-induced epidermal responses in regenerative organisms traditionally being restricted to the wound site. Here, we investigate the effect of amputation on long-range epidermal permeability in two evolutionarily distant, regenerative organisms: axolotls and planarians. We find that amputation triggers a long-range increase in epidermal permeability in axolotls, accompanied by a long-range epidermal downregulation in MAPK signaling. Additionally, we provide functional evidence that pharmacologically inhibiting MAPK signaling in regenerating planarians increases long-range epidermal permeability. These findings advance our knowledge of body-wide changes due to amputation in regenerative organisms and warrant further study on whether epidermal permeability dysregulation in the context of amputation may lead to pathology in both regenerative and non-regenerative organisms. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=167 SRC="FIGDIR/small/610385v2_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@81b022org.highwire.dtl.DTLVardef@52c2e9org.highwire.dtl.DTLVardef@17a5f93org.highwire.dtl.DTLVardef@118b8f6_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2019

Asymmetric Hapln1a drives regionalised cardiac ECM expansion and promotes heart morphogenesis during zebrafish development

The mature vertebrate heart develops from a simple linear cardiac tube during early development through a series of highly asymmetric morphogenetic processes including cardiac looping and chamber ballooning. While the directionality of heart morphogenesis is partly controlled by embryonic laterality signals, previous studies have suggested that these extrinsic laterality cues interact with tissue-intrinsic signals in the heart to ensure robust asymmetric cardiac morphogenesis. Using live in vivo imaging of zebrafish embryos we describe a left-sided, chamber-specific expansion of the extracellular matrix (ECM) between the myocardium and endocardium at early stages of heart morphogenesis. We use Tomo-seq, a spatial transcriptomic approach, to identify transient and regionalised expression of hyaluronan and proteoglycan link protein 1a (hapln1a), encoding an ECM cross-linking protein, in the heart tube prior to cardiac looping overlapping with regionalised ECM expansion. Loss- and gain-of-function experiments demonstrate that regionalised Hapln1a promotes heart morphogenesis through regional modulation of ECM thickness in the heart tube. Finally, we show that while induction of asymmetric hapln1a expression is independent of embryonic left-right asymmetry, these laterality cues are required to orient the hapln1a-expressing cells asymmetrically along the left-right axis of the heart tube. Together, we propose a model whereby laterality cues position hapln1a expression on the left of the heart tube, and this asymmetric Hapln1a deposition drives ECM asymmetry and subsequently promotes robust asymmetric cardiac morphogenesis.

developmental biology↗

bioRxiv2018

foxc1a and foxc1b differentially regulate angiogenesis from arteries and veins by modulating Vascular Endothelial Growth Factor signalling

The forkhead transcription factors Foxc1 and Foxc2 are essential to establish intact vascular networks in mammals. How these genes interact with endothelial signalling pathways to exert their functions remains incompletely understood. We have generated novel zebrafish mutants in foxc1a and foxc1b, the zebrafish orthologues of mammalian Foxc1, to determine their function during angiogenesis. foxc1a mutants display abnormal formation of cranial veins including the primordial hindbrain channels (PHBC), reduced Vascular Endothelial Growth Factor (VEGF) receptor expression in these and loss of central arteries. foxc1b mutants are normal, whereas foxc1a; foxc1b double mutants exhibit ectopic angiogenesis from trunk segmental arteries. Dll4/Notch signalling is reduced in foxc1a; foxc1b double mutant arteries and ectopic angiogenesis can be suppressed by induction of Notch or inhibition of Vegfc signalling. We conclude that foxc1a and foxc1b play compensatory and context-dependent roles to co-ordinate angiogenesis by promoting venous sprouting via induction of VEGF receptor expression whilst antagonising arterial sprouting by inducing Dll4/Notch signalling. foxc1a/b mediated induction of both pro- and anti-angiogenic axes of VEGF-Dll4/Notch negative feedback imparts competition to balance arterial and venous angiogenesis within developing vascular beds.\n\nSummary Statementfoxc1a and foxc1b promote angiogenesis from veins and suppress angiogenesis from arteries by promoting competing pro-angiogenic Vascular Endothelial Growth Factor signalling, and anti-angiogenic Dll4/Notch signalling in zebrafish embryos.

developmental biology↗