Multi-species comparisons of snakes identify coordinated signaling networks underlying post-feeding intestinal regeneration

Several snake species that feed infrequently in nature have evolved the ability to massively upregulate intestinal form and function with each meal. While fasting, these snakes downregulate intestinal form and function and upon feeding restore intestinal structure and function through major increases in cell growth and proliferation, metabolism, and upregulation of digestive function. Previous studies have identified changes in gene expression that underlie this regenerative growth of the python intestine, but the unique features that differentiate this extreme regenerative growth from non-regenerative post-feeding responses exhibited by snakes that feed more frequently remain unclear. Here, we leveraged variation in regenerative capacity across three snake species – two distantly-related lineages (Crotalus and Python) that experience regenerative growth, and one (Nerodia) that does not – to infer molecular mechanisms underlying intestinal regeneration using transcriptomic and proteomic approaches. Utilizing a comparative approach, we identify a suite of growth, stress response, and DNA damage response signaling pathways with inferred activity specifically in regenerating species, and propose a hypothesis model of interactivity between these pathways that may drive regenerative intestinal growth in snakes.