Foxg1promotes olfactory neurogenesis by antagonizingGdf11

Abstract

Foxg1, a winged-helix transcription factor, promotes the development of anterior neural structures; in mice lacking Foxg1, development of the cerebral hemispheres and olfactory epithelium (OE) is severely reduced. It has been suggested that Foxg1 acts by positively regulating the expression of growth factors, such as Fgf8, which support neurogenesis. However, Foxg1 also binds Smad transcriptional complexes, allowing it to negatively regulate the effects of TGFβ family ligands. Here, we provide evidence that this latter effect explains much of the ability of Foxg1 to drive neurogenesis in the OE. We show that Foxg1 is expressed in developing OE at the same time as the gene encoding growth differentiation factor 11 (Gdf11), a TGFβ family member that mediates negative-feedback control of OE neurogenesis. Mutations in Gdf11 rescue, to a considerable degree, the major defects in Foxg1-/- OE,including the early, severe loss of neural precursors and olfactory receptor neurons, and the subsequent collapse of both neurogenesis and nasal cavity formation. Rescue is gene-dosage dependent, with loss of even one allele of Gdf11 restoring substantial neurogenesis. Notably, we find no evidence for a disruption of Fgf8 expression in Foxg1-/- OE. However, we do observe both a failure of expression of follistatin (Fst), which encodes a secreted Gdf11 antagonist normally expressed in and around OE, and an increase in the expression of Gdf11 itself within the remaining OE in these mutants. Fst expression is rescued in Foxg1-/-;Gdf11-/- and Foxg1-/-;Gdf11+/- mice. These data suggest that the influence of Foxg1 on Gdf11-mediated negative feedback of neurogenesis may be both direct and indirect. In addition, defects in development of the cerebral hemispheres in Foxg1-/- mice are not rescued by mutations in Gdf11, nor is Gdf11 expressed at high levels within these structures. Thus, the pro-neurogenic effects of Foxg1are likely to be mediated through different signaling pathways in different parts of the nervous system.

Opposing Fgf and Bmp activities regulate the specification of olfactory sensory and respiratory epithelial cell fates

“…Accordingly, inhibition of Bmp activity resulted in a decrease of pSmad1/5/8, which promoted the generation of sensory epithelial cells at the expense of respiratory epithelial cells. In line with our findings, recent results have suggested that Fgf-induced Foxg1 (Storm et al, 2006) promotes the generation of olfactory sensory neurons via upregulation of the Tgfb antagonist follistatin, which antagonizes Gdf11 activity in the olfactory pit (Kawauchi et al, 2009). In summary, we find that at olfactory placodal and pit stages, Fgf and Bmp signals act in an opposing manner to regulate sensory versus respiratory epithelial cell fate decision.…”

A missense mutation within the fork-head domain of the forkhead box G1 Gene (FOXG1) affects its nuclear localization

“…After transfection and collection of (GFP+)-transfected using a FACScan flow cytometer, total RNAs were extracted, converted to cDNA, and CDKN1A expression was studied by real-time RT-PCR. As reported in previous reports [Seoane et al 2004;Kawauchi et al 2009;Chan et al 2009], we first observed that overexpression of the wild-type protein FOXG1 in cells results in a decrease (~40%) of CDKN1A expression as compared with untransfected cells (data not shown). Secondly, we showed that overexpression of the p.R244C mutant results in an increase (Fig.…”

“…Target genes include cell cycle inhibitors, such as the cyclin-dependent kinase inhibitor 1A (p21, Cip1) (CDKN1A) gene [Seoane et al 2004;Kawauchi et al 2009;Chan et al 2009]. FoxG1 is known to be a potent inhibitor of the transforming growth factor (TGF) β-regulated signalling by inhibiting the TGFβ-dependent transcription of the CDKN1A gene, encoding a cell cycle protein that may induce cell cycle exit in neural precursors [Siegenthaler and Miller, 2005].…”

RGMB and neogenin control cell differentiation in the developing olfactory epithelium

“…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).…”

“…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).…”