Reversible developmental stasis in response to nutrient availability in theXenopus laevisCNS

Abstract

Many organisms confront intermittent nutrient restriction (NR), but the mechanisms to cope with nutrient fluctuations during development are not well understood. This is particularly true of the brain, the development and function of which is energy intensive. Here we examine the effects of nutrient availability on visual system development in Xenopus laevis tadpoles. During the first week of development, tadpoles draw nutrients from maternally provided yolk. Upon yolk depletion, animals forage for food. By altering access to external nutrients after yolk depletion, we identified a period of reversible stasis during tadpole development. We demonstrate that NR results in developmental stasis characterized by a decrease in overall growth of the animals, a failure to progress through developmental stages, and a decrease in volume of the optic tectum. During NR, neural progenitors virtually cease proliferation, but tadpoles swim and behave normally. Introducing food after temporary NR increased neural progenitor cell proliferation more than 10-fold relative to NR tadpoles, and cell proliferation was comparable to that of fed counterparts 1 week after delayed feeding. Delayed feeding also rescued NR-induced body length and tectal volume deficits and partially rescued developmental progression defects. Tadpoles recover from developmental stasis if food is provided within the first 9 days of NR, after which access to food fails to increase cell proliferation. These results show that early stages of tadpole brain development are acutely sensitive to fluctuations in nutrient availability and that NR induces developmental stasis from which animals can recover if food becomes available within a critical window.

Nutrient restriction causes reversible G2 arrest in Xenopus neural progenitors

“…Studies in zebrafish indicate that neural cell proliferation is inhibited under NR conditions, and neural progenitor cells (NPCs) can resume proliferation when food is available (Benítez-Santana et al, 2017). We have shown that Xenopus laevis tadpoles that have been deprived of external nutrients cease proliferation in the developing brain, and that cell division resumes upon re-introduction of food (McKeown et al, 2017). Completely depriving younger tadpoles of food by surgically removing the yolk stores halts NPC proliferation in the developing retina (Love et al, 2014), indicating that proliferative stasis can occur across different neuronal tissues in the tadpole.…”

“…Vascular endothelial cells also proliferate but can be distinguished from NPCs based on their distinct morphology and location (Lau et al, 2017;Rovainen and Kakarala, 1989;Sharma and Cline, 2010). We have previously shown that tectal NPCs stop dividing when the animal enters a period of developmental stasis in response to nutrient restriction (McKeown et al, 2017). To understand the cellular responses to nutrient availability in the brain, we first investigated NPC proliferation during nutrientrestricted and fed conditions at early stages of brain development.…”

“…Our previous work showed that during nutrient restriction-induced developmental stasis, animals reduce CNS NPC proliferation. Upon reintroduction of external nutrients, nutrient-restricted animals exit developmental stasis and resume development, and importantly, food re-initiates tectal NPC proliferation (McKeown et al, 2017). To understand the mechanisms by which nutrient-restricted progenitors re-initiate proliferation, we performed a series of experiments to test the proliferative response to re-introduction of food in a controlled manner.…”

“…We address these open questions in Xenopus; we have previously demonstrated that Xenopus laevis tadpoles enter a period of developmental stasis in response to nutrient restriction (McKeown et al, 2017). During stasis, Xenopus tadpoles continue to swim and exhibit visual avoidance behaviors, but rates of overall body growth and brain development decrease, and NPC proliferation halts.…”

Phenotypic Switching Resulting From Developmental Plasticity: Fixed or Reversible?

“…Nutrient restriction during the first week of development in larval Xenopus laevis results in the failure of neural progenitors to proliferate, but this effect can be corrected by a return to normal nutrition, affected by a subsequent 10-fold increase in cell proliferation stimulated by feeding (McKeown et al, 2017). Feeding also rescues nutrition restricted-induced decreases body length and brain tectal volume.…”