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Activin and GDF11 collaborate in feedback control of neuroepithelial stem cell proliferation and fate.

ABSTRACT: Studies of the olfactory epithelium model system have demonstrated that production of neurons is regulated by negative feedback. Previously, we showed that a locally produced signal, the TGF? superfamily ligand GDF11, regulates the genesis of olfactory receptor neurons by inhibiting proliferation of the immediate neuronal precursors (INPs) that give rise to them. GDF11 is antagonized by follistatin (FST), which is also produced locally. Here, we show that Fst(-/-) mice exhibit dramatically decreased neurogenesis, a phenotype that can only be partially explained by increased GDF11 activity. Instead, a second FST-binding factor, activin ?B (ACT?B), inhibits neurogenesis by a distinct mechanism: whereas GDF11 inhibits expansion of INPs, ACT?B inhibits expansion of stem and early progenitor cells. We present data supporting the concept that these latter cells, previously considered two distinct types, constitute a dynamic stem/progenitor population in which individual cells alternate expression of Sox2 and/or Ascl1. In addition, we demonstrate that interplay between ACT?B and GDF11 determines whether stem/progenitor cells adopt a glial versus neuronal fate. Altogether, the data indicate that the transition between stem cells and committed progenitors is neither sharp nor irreversible and that GDF11, ACT?B and FST are crucial components of a circuit that controls both total cell number and the ratio of neuronal versus glial cells in this system. Thus, our findings demonstrate a close connection between the signals involved in the control of tissue size and those that regulate the proportions of different cell types.

SUBMITTER: Gokoffski KK

PROVIDER: S-EPMC3171217 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Activin and GDF11 collaborate in feedback control of neuroepithelial stem cell proliferation and fate.

Gokoffski Kimberly K KK Wu Hsiao-Huei HH Beites Crestina L CL Kim Joon J Kim Euiseok J EJ Matzuk Martin M MM Johnson Jane E JE Lander Arthur D AD Calof Anne L AL

Development (Cambridge, England) 20110818 19

Studies of the olfactory epithelium model system have demonstrated that production of neurons is regulated by negative feedback. Previously, we showed that a locally produced signal, the TGFβ superfamily ligand GDF11, regulates the genesis of olfactory receptor neurons by inhibiting proliferation of the immediate neuronal precursors (INPs) that give rise to them. GDF11 is antagonized by follistatin (FST), which is also produced locally. Here, we show that Fst(-/-) mice exhibit dramatically decre ...[more]

PMID: 21852401

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Project description:BackgroundIn planarian flatworms, the mechanisms underlying the activity of collectively pluripotent adult stem cells (neoblasts) and their descendants can now be studied from the level of the individual gene to the entire animal. Flatworms maintain startling developmental plasticity and regenerative capacity in response to variable nutrient conditions or injury. We develop a model for cell dynamics in such animals, assuming that fully differentiated cells exert feedback control on neoblast activity.ResultsOur model predicts a number of whole organism level and general cell biological and behaviours, some of which have been empirically observed or inferred in planarians and others that have not. As previously observed empirically we find: 1) a curvilinear relationship between external food and planarian steady state size; 2) the fraction of neoblasts in the steady state is constant regardless of planarian size; 3) a burst of controlled apoptosis during regeneration after amputation as the number of differentiated cells are adjusted towards their homeostatic/steady state level. In addition our model describes the following properties that can inform and be tested by future experiments: 4) the strength of feedback control from differentiated cells to neoblasts (i.e. the activity of the signalling system) and from neoblasts on themselves in relation to absolute number depends upon the level of food in the environment; 5) planarians adjust size when food level reduces initially through increased apoptosis and then through a reduction in neoblast self-renewal activity; 6) following wounding or excision of differentiated cells, different time scales characterize both recovery of size and the two feedback functions; 7) the temporal pattern of feedback controls differs noticeably during recovery from a removal or neoblasts or a removal of differentiated cells; 8) the signaling strength for apoptosis of differentiated cells depends upon both the absolute and relative deviations of the number of differentiated cells from their homeostatic level; and 9) planaria prioritize resource use for cell divisions.ConclusionsWe offer the first analytical framework for organizing experiments on planarian flatworm stem cell dynamics in a form that allows models to be compared with quantitative cell data based on underlying molecular mechanisms and thus facilitate the interplay between empirical studies and modeling. This framework is the foundation for studying cell migration during wound repair, the determination of homeostatic levels of differentiated cells by natural selection, and stochastic effects.

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Activin and GDF11 collaborate in feedback control of neuroepithelial stem cell proliferation and fate.

Publications

Activin and GDF11 collaborate in feedback control of neuroepithelial stem cell proliferation and fate.

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