Document Detail


Foxg1 promotes olfactory neurogenesis by antagonizing Gdf11.
MedLine Citation:
PMID:  19297409     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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 TGFbeta 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 TGFbeta 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 Foxg1 are likely to be mediated through different signaling pathways in different parts of the nervous system.
Authors:
Shimako Kawauchi; Joon Kim; Rosaysela Santos; Hsiao-Huei Wu; Arthur D Lander; Anne L Calof
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2009-03-18
Journal Detail:
Title:  Development (Cambridge, England)     Volume:  136     ISSN:  0950-1991     ISO Abbreviation:  Development     Publication Date:  2009 May 
Date Detail:
Created Date:  2009-04-13     Completed Date:  2009-06-25     Revised Date:  2014-09-09    
Medline Journal Info:
Nlm Unique ID:  8701744     Medline TA:  Development     Country:  England    
Other Details:
Languages:  eng     Pagination:  1453-64     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Bone Morphogenetic Proteins / antagonists & inhibitors*,  genetics,  metabolism*
Cerebral Cortex / embryology,  metabolism
Cyclin-Dependent Kinase Inhibitor p21 / genetics,  metabolism
Down-Regulation
Epithelium / embryology,  innervation,  metabolism
Fibroblast Growth Factor 8 / genetics,  metabolism
Follistatin / genetics,  metabolism
Forkhead Transcription Factors / deficiency,  genetics,  metabolism*
Gene Expression Regulation, Developmental
Growth Differentiation Factors / antagonists & inhibitors*,  genetics,  metabolism*
Mice
Mice, Inbred C57BL
Mice, Knockout
Mutation / genetics
Nasal Mucosa / metabolism
Nerve Tissue Proteins / deficiency,  genetics,  metabolism*
Neurogenesis*
Olfactory Bulb / embryology*,  metabolism*
Signal Transduction
Grant Support
ID/Acronym/Agency:
1P01-HD052860/HD/NICHD NIH HHS; DC03583/DC/NIDCD NIH HHS; P30 CA062203/CA/NCI NIH HHS; P50 GM076516/GM/NIGMS NIH HHS; P50 GMO-76516//PHS HHS; R01 DC003583/DC/NIDCD NIH HHS
Chemical
Reg. No./Substance:
0/Bone Morphogenetic Proteins; 0/Cdkn1a protein, mouse; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/Fgf8 protein, mouse; 0/Follistatin; 0/Forkhead Transcription Factors; 0/Foxg1 protein, mouse; 0/Gdf11 protein, mouse; 0/Growth Differentiation Factors; 0/Nerve Tissue Proteins; 148997-75-5/Fibroblast Growth Factor 8
Comments/Corrections

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