title: 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 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 decreased neurogenesis, a phenotype that can only be partially explained by increased GDF11 activity. Instead, a second FST-binding factor, activin βB (ACTβB), inhibits neurogenesis by a distinct mechanism: whereas GDF11 inhibits expansion of INPs, ACTβB 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 ACTβB 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, ACTβB 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.
authors.affiliation: Department of Developmental & Cell Biology, University of California, Irvine, CA 92697, USA.
authors.forename: Kimberly K
authors.initials: KK
authors.lastname: Gokoffski
authors.forename: Hsiao-Huei
authors.initials: HH
authors.lastname: Wu
authors.forename: Crestina L
authors.initials: CL
authors.lastname: Beites
authors.forename: Joon
authors.initials: J
authors.lastname: Kim
authors.forename: Euiseok J
authors.initials: EJ
authors.lastname: Kim
authors.forename: Martin M
authors.initials: MM
authors.lastname: Matzuk
authors.forename: Jane E
authors.initials: JE
authors.lastname: Johnson
authors.forename: Arthur D
authors.initials: AD
authors.lastname: Lander
authors.forename: Anne L
authors.initials: AL
authors.lastname: Calof
mesh_terms: D028341:Activins / Q000502:physiology*; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D019070:Cell Lineage; D049109:Cell Proliferation; D025461:Feedback, Physiological; D038681:Follistatin / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D055412:Growth Differentiation Factors / Q000378:metabolism*; D028322:Inhibin-beta Subunits / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D046569:Neuroepithelial Cells / Q000166:cytology*; D009457:Neuroglia / Q000166:cytology; D009474:Neurons / Q000378:metabolism; D009831:Olfactory Mucosa / Q000166:cytology*; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D028341:Activins; D051792:Basic Helix-Loop-Helix Proteins; D019485:Bone Morphogenetic Proteins; D038681:Follistatin; D055412:Growth Differentiation Factors; D028322:Inhibin-beta Subunits; D055748:SOXB1 Transcription Factors; C499317:Ascl1 protein, mouse; C119153:Gdf11 protein, mouse; C527783:Sox2 protein, mouse; C103008:inhibin beta A subunit