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

Abstract

SUMMARYStudies 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.

RGMB and neogenin control cell differentiation in the developing olfactory epithelium

“…To assess this in Neo1 −/− embryos, we counted the number of SOX2-positive cells in the apical region of the OE after confirming that these cells express the SUS cell marker cytokeratin 18 (CK18, or KRT18), as previously described ( Fig. 4B) (Gokoffski et al, 2011;Packard et al, 2011). We observed a significant increase in the number of SOX2-positive cells in Neo1 −/− embryos (Fig.…”

“…The relative levels of expression of the transcription factors ASCL1 and SOX2 appears to underlie cell fate bias, with cells that maintain SOX2 expression committing to a glial fate (Gokoffski et al, 2011;Krolewski et al, 2012). Several secreted factors have been identified so far as regulators of cell fate choice in the OE, including activins, BMPs, GDF11 and follistatin (Gokoffski et al, 2011;Kawauchi et al, 2009;Shou et al, 2000;Wu et al, 2003).…”

“…The relative levels of expression of the transcription factors ASCL1 and SOX2 appears to underlie cell fate bias, with cells that maintain SOX2 expression committing to a glial fate (Gokoffski et al, 2011;Krolewski et al, 2012). Several secreted factors have been identified so far as regulators of cell fate choice in the OE, including activins, BMPs, GDF11 and follistatin (Gokoffski et al, 2011;Kawauchi et al, 2009;Shou et al, 2000;Wu et al, 2003). In addition to these proteins, members of the Notch family of receptors and their transmembrane ligands of the Delta family are expressed in the OE and have been proposed to regulate the development and maintenance of OE cell populations (Carson et al, 2006;Cau et al, 2000;Schwarting et al, 2007).…”

“…In addition to producing neurons, ASCL1-expressing progenitor cells also give rise directly to SUS cells, which form a monolayer in the apical region of the OE, indicating that signaling mechanisms must be in place to control cell fate choice in these bipotential progenitors (Gokoffski et al, 2011;Krolewski et al, 2012). While several members of the TGFβ family of molecules have been implicated in the generation and survival of ORNs, much less is known about the signals that regulate the production of SUS cells (Gokoffski et al, 2011;Kawauchi et al, 2009Kawauchi et al, , 2005Wu et al, 2003).…”

“…While several members of the TGFβ family of molecules have been implicated in the generation and survival of ORNs, much less is known about the signals that regulate the production of SUS cells (Gokoffski et al, 2011;Kawauchi et al, 2009Kawauchi et al, , 2005Wu et al, 2003).…”