Abstract
BackgroundPrevious studies examining post-feeding organ regeneration in the Burmese python (Python molurus bivittatus) have identified thousands of genes that are significantly differentially regulated during this process. However, substantial gaps remain in our understanding of coherent mechanisms and specific growth pathways that underlie these rapid and extensive shifts in organ form and function. Here we addressed these gaps by comparing gene expression in the Burmese python heart, liver, kidney, and small intestine across pre- and post-feeding time points (fasted, one day post-feeding, and four days post-feeding), and by conducting detailed analyses of molecular pathways and predictions of upstream regulatory molecules across these organ systems.ResultsIdentified enriched canonical pathways and upstream regulators indicate that while downstream transcriptional responses are fairly tissue specific, a suite of core pathways and upstream regulator molecules are shared among responsive tissues. Pathways such as mTOR signaling, PPAR/LXR/RXR signaling, and NRF2-mediated oxidative stress response are significantly differentially regulated in multiple tissues, indicative of cell growth and proliferation along with coordinated cell-protective stress responses. Upstream regulatory molecule analyses identify multiple growth factors, kinase receptors, and transmembrane receptors, both within individual organs and across separate tissues. Downstream transcription factors MYC and SREBF are induced in all tissues.ConclusionsThese results suggest that largely divergent patterns of post-feeding gene regulation across tissues are mediated by a core set of higher-level signaling molecules. Consistent enrichment of the NRF2-mediated oxidative stress response indicates this pathway may be particularly important in mediating cellular stress during such extreme regenerative growth.
Highlights
Previous studies examining post-feeding organ regeneration in the Burmese python (Python molurus bivittatus) have identified thousands of genes that are significantly differentially regulated during this process
Major gaps remain in our understanding of the specific mechanisms and growth pathways that are responsible for driving these extreme shifts in Burmese python organ size and function, as well as how these mechanisms may vary across different organ systems
MTOR and other growth pathways underlying organ growth Across the four organs examined, we found evidence for the involvement of the mTOR signaling pathway as a key integrator of growth signals underlying post-feeding regenerative organ growth. This pathway integrates processes for the use of energy and nutrients to regulate growth and homeostasis [30]. mTOR interacts with multiple other pathways, including PI3K/AKT, several lipid metabolism and signaling pathways [30, 31], and the NRF2-mediated oxidative stress response [32, 33] – all of which are active in multiple organs during growth (Figs. 3–5). mTOR complex 1 is the most well-characterized of the two mTOR complexes and integrates signaling from growth factors, energy status, oxygen, and amino acids to promote cell growth when activated [31]
Summary
Previous studies examining post-feeding organ regeneration in the Burmese python (Python molurus bivittatus) have identified thousands of genes that are significantly differentially regulated during this process. Substantial gaps remain in our understanding of coherent mechanisms and specific growth pathways that underlie these rapid and extensive shifts in organ form and function We addressed these gaps by comparing gene expression in the Burmese python heart, liver, kidney, and small intestine across pre- and post-feeding time points (fasted, one day post-feeding, and four days post-feeding), and by conducting detailed analyses of molecular pathways and predictions of upstream regulatory molecules across these organ systems. The ability to massively downregulate metabolic and physiological functions during extended periods of fasting has evolved in multiple species of snakes This downregulation of physiological form includes the atrophy of organs such as the heart, kidney, liver, and small intestine. Major gaps remain in our understanding of the specific mechanisms and growth pathways that are responsible for driving these extreme shifts in Burmese python organ size and function, as well as how these mechanisms may vary across different organ systems
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