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Metabolomic insights into system-wide coordination of vertebrate metamorphosis.

Ichu TA, Han J, Borchers CH, Lesperance M, Helbing CC - BMC Dev. Biol. (2014)

Bottom Line: The majority of the detected metabolites (74%) showed statistically significant abundance changes (padj < 0.001) between metamorphic stages.We observed extensive remodelling of five core metabolic pathways: arginine and purine/pyrimidine, cysteine/methionine, sphingolipid, and eicosanoid metabolism and the urea cycle, and found evidence for a major role for lipids during this postembryonic process.Metabolites traditionally linked to human disease states were found to have biological linkages to the system-wide changes occuring during the events leading up to overt morphological change.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC V8W 2Y2, Canada. chelbing@uvic.ca.

ABSTRACT

Background: After completion of embryogenesis, many organisms experience an additional obligatory developmental transition to attain a substantially different juvenile or adult form. During anuran metamorphosis, the aquatic tadpole undergoes drastic morphological changes and remodelling of tissues and organs to become a froglet. Thyroid hormones are required to initiate the process, but the mechanism whereby the many requisite changes are coordinated between organs and tissues is poorly understood. Metabolites are often highly conserved biomolecules between species and are the closest reflection of phenotype. Due to the extensive distribution of blood throughout the organism, examination of the metabolites contained therein provides a system-wide overview of the coordinated changes experienced during metamorphosis. We performed an untargeted metabolomic analysis on serum samples from naturally-metamorphosing Rana catesbeiana from tadpoles to froglets using ultraperformance liquid chromatography coupled to a mass spectrometer. Total and aqueous metabolite extracts were obtained from each serum sample to select for nonpolar and polar metabolites, respectively, and selected metabolites were validated by running authentic compounds.

Results: The majority of the detected metabolites (74%) showed statistically significant abundance changes (padj < 0.001) between metamorphic stages. We observed extensive remodelling of five core metabolic pathways: arginine and purine/pyrimidine, cysteine/methionine, sphingolipid, and eicosanoid metabolism and the urea cycle, and found evidence for a major role for lipids during this postembryonic process. Metabolites traditionally linked to human disease states were found to have biological linkages to the system-wide changes occuring during the events leading up to overt morphological change.

Conclusions: To our knowledge, this is the first wide-scale metabolomic study of vertebrate metamorphosis identifying fundamental pathways involved in the coordination of this important developmental process and paves the way for metabolomic studies on other metamorphic systems including fish and insects.

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Significant abundance changes of the metabolites in the eicosanoid metabolism pathway. The superscripts indicate that the metabolites have the same mass and cannot be differentiated. (A) Overall abundance changes of the metabolites. (B) Progression of the abundance change of the metabolites relative to the premetamorphic stage (TK VI–X). Refer to Figure 4 legend for details. Metabolites with the same superscript letter (a, b, or c) share the same mass and cannot be distinguished from each other.
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Figure 12: Significant abundance changes of the metabolites in the eicosanoid metabolism pathway. The superscripts indicate that the metabolites have the same mass and cannot be differentiated. (A) Overall abundance changes of the metabolites. (B) Progression of the abundance change of the metabolites relative to the premetamorphic stage (TK VI–X). Refer to Figure 4 legend for details. Metabolites with the same superscript letter (a, b, or c) share the same mass and cannot be distinguished from each other.

Mentions: Arachidonic acid-derived eicosanoids, including prostaglandins (PG) and leukotrienes (LT), act as signalling molecules that control diverse biological responses such as vascular homeostasis and inflammatory responses to tissue remodelling [67]. The metabolites in the eicosanoid metabolism pathway showed a significant abundance change (Figures 12 and 13). PG A, B, C, and J2 could not be distinguished because they are structural isomers. Similarly, other groups of metabolites were indistinguishable including PG D, E, H2, LTB4, and 20-OH-LTB4. Anurans have substantially different immune systems at the larval and frog stages [68]. It has been hypothesized that the development of molecules specific to the frog stage (adult hemoglobin, adult-type keratin, the urea cycle enzyme L-arginase, etc.) could elicit self-destructive immune responses during metamorphosis [69]. To avoid this, amphibians self-destruct their lymphocytes [68], which is supported by the fact that amphibian metamorphosis is not characterized by autoimmune tissue destruction. In Xenopus laevis, a decline in lymphocytes during metamorphosis has been observed in the spleen, thymus, and liver [69-71]. This hypothesized remodelling of the immune system in anurans may explain the dynamic change in the eicosanoid metabolism pathway that occurs during metamorphosis.


Metabolomic insights into system-wide coordination of vertebrate metamorphosis.

Ichu TA, Han J, Borchers CH, Lesperance M, Helbing CC - BMC Dev. Biol. (2014)

Significant abundance changes of the metabolites in the eicosanoid metabolism pathway. The superscripts indicate that the metabolites have the same mass and cannot be differentiated. (A) Overall abundance changes of the metabolites. (B) Progression of the abundance change of the metabolites relative to the premetamorphic stage (TK VI–X). Refer to Figure 4 legend for details. Metabolites with the same superscript letter (a, b, or c) share the same mass and cannot be distinguished from each other.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3928663&req=5

Figure 12: Significant abundance changes of the metabolites in the eicosanoid metabolism pathway. The superscripts indicate that the metabolites have the same mass and cannot be differentiated. (A) Overall abundance changes of the metabolites. (B) Progression of the abundance change of the metabolites relative to the premetamorphic stage (TK VI–X). Refer to Figure 4 legend for details. Metabolites with the same superscript letter (a, b, or c) share the same mass and cannot be distinguished from each other.
Mentions: Arachidonic acid-derived eicosanoids, including prostaglandins (PG) and leukotrienes (LT), act as signalling molecules that control diverse biological responses such as vascular homeostasis and inflammatory responses to tissue remodelling [67]. The metabolites in the eicosanoid metabolism pathway showed a significant abundance change (Figures 12 and 13). PG A, B, C, and J2 could not be distinguished because they are structural isomers. Similarly, other groups of metabolites were indistinguishable including PG D, E, H2, LTB4, and 20-OH-LTB4. Anurans have substantially different immune systems at the larval and frog stages [68]. It has been hypothesized that the development of molecules specific to the frog stage (adult hemoglobin, adult-type keratin, the urea cycle enzyme L-arginase, etc.) could elicit self-destructive immune responses during metamorphosis [69]. To avoid this, amphibians self-destruct their lymphocytes [68], which is supported by the fact that amphibian metamorphosis is not characterized by autoimmune tissue destruction. In Xenopus laevis, a decline in lymphocytes during metamorphosis has been observed in the spleen, thymus, and liver [69-71]. This hypothesized remodelling of the immune system in anurans may explain the dynamic change in the eicosanoid metabolism pathway that occurs during metamorphosis.

Bottom Line: The majority of the detected metabolites (74%) showed statistically significant abundance changes (padj < 0.001) between metamorphic stages.We observed extensive remodelling of five core metabolic pathways: arginine and purine/pyrimidine, cysteine/methionine, sphingolipid, and eicosanoid metabolism and the urea cycle, and found evidence for a major role for lipids during this postembryonic process.Metabolites traditionally linked to human disease states were found to have biological linkages to the system-wide changes occuring during the events leading up to overt morphological change.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC V8W 2Y2, Canada. chelbing@uvic.ca.

ABSTRACT

Background: After completion of embryogenesis, many organisms experience an additional obligatory developmental transition to attain a substantially different juvenile or adult form. During anuran metamorphosis, the aquatic tadpole undergoes drastic morphological changes and remodelling of tissues and organs to become a froglet. Thyroid hormones are required to initiate the process, but the mechanism whereby the many requisite changes are coordinated between organs and tissues is poorly understood. Metabolites are often highly conserved biomolecules between species and are the closest reflection of phenotype. Due to the extensive distribution of blood throughout the organism, examination of the metabolites contained therein provides a system-wide overview of the coordinated changes experienced during metamorphosis. We performed an untargeted metabolomic analysis on serum samples from naturally-metamorphosing Rana catesbeiana from tadpoles to froglets using ultraperformance liquid chromatography coupled to a mass spectrometer. Total and aqueous metabolite extracts were obtained from each serum sample to select for nonpolar and polar metabolites, respectively, and selected metabolites were validated by running authentic compounds.

Results: The majority of the detected metabolites (74%) showed statistically significant abundance changes (padj < 0.001) between metamorphic stages. We observed extensive remodelling of five core metabolic pathways: arginine and purine/pyrimidine, cysteine/methionine, sphingolipid, and eicosanoid metabolism and the urea cycle, and found evidence for a major role for lipids during this postembryonic process. Metabolites traditionally linked to human disease states were found to have biological linkages to the system-wide changes occuring during the events leading up to overt morphological change.

Conclusions: To our knowledge, this is the first wide-scale metabolomic study of vertebrate metamorphosis identifying fundamental pathways involved in the coordination of this important developmental process and paves the way for metabolomic studies on other metamorphic systems including fish and insects.

Show MeSH
Related in: MedlinePlus