A nutrient-sensitive restriction point is active during retinal progenitor cell differentiation

Abstract

In many growing tissues, slowly dividing stem cells give rise to rapidly proliferating progenitors that eventually exit the cell cycle and differentiate. Growth rates are limited by nutrient availability, but it is unclear which steps of the proliferation-differentiation programme are particularly sensitive to fuel supplies. We examined how nutrient deprivation (ND) affects stem and progenitor cells in the ciliary marginal zone (CMZ) of the amphibian retina, a well-characterised neurogenic niche. We show that ND specifically blocks the proliferation and differentiation of progenitor cells through an mTORmediated mechanism. By contrast, the identity and proliferation of retinal stem cells are insensitive to ND and mTOR inhibition. Refeeding starved retinas in vitro rescues both proliferation and differentiation, and activation of mTOR is sufficient to stimulate differentiation even in ND retinas. These results suggest that an mTOR-mediated restriction point operates in vivo to couple nutrient abundance to the proliferation and differentiation programme in retinal progenitor cells.

Nucleoside diphosphate kinases (NDPKs) in animal development

“…Importantly, NDPK knockdown alone in the fully fed state could neither alter vectorial motion nor change gross cell morphology during differentiation. This interesting observation is consistent with the roles of NDPK in hypoxia responsiveness, nutrition and cell-fate specification [81]. Next, these authors studied nutrient uptake in single Dictyostelium cells either plated onto a flat-bed on top of bacterial lawns as a food source (macropinocytosis assay) or, by placing these single cells in a liquid environment, exposed to micronutrient broths of soluble factors such as amino acids (axenic culture) [88].…”

“…This unifying concept awaits confirmation but fits with proposed relationships between NDPK and hypoxia sensing, and links NDPKs to nutrition and cell proliferation [81].…”

“…During frog retinal development, stem cells generate the neuronal precursor cells that exit the cell cycle immediately before their terminal and cell-fate determination step [81,82]. Next, these cells differentiate to determine the final composition of mature retinal cells of different subtypes.…”

Reversible developmental stasis in response to nutrient availability in theXenopus laevisCNS

“…Indeed, cell size in many organisms is regulated via an mTOR-dependent mechanism, a pathway that regulates protein synthesis downstream of stress responses and nutrient signaling (Efeyan et al, 2015;Fingar et al, 2002;Lee da, 2015;Sofer et al, 2005). In X. laevis, animals that have been completely nutrient deprived by surgically removing the intestine with its yolk stores halt progenitor cell proliferation in the developing retina via an mTOR-dependent mechanism (Love et al, 2014). It will be interesting to determine whether the NR-dependent developmental stasis we describe in the X. laevis brain acts via an mTOR-dependent mechanism as well.…”

Metabolism meets development at Wiston House

“…Even though they have access to oxygen, the stem cells of the CMZ are fermentative, reminiscent of the 'Warburg effect' seen in cancer. He then presented evidence for a nutritionsensitive restriction point for proliferation and differentiation in the CMZ (Love et al, 2014) and that the hypoxia-activated HIF1 pathway can overcome this restriction (Khaliullina et al, 2016). These types of results may give insights into how and why dedifferentiated cancer cells rely less on respiration compared with differentiated cells.…”