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Fgf15-mediated control of neurogenic and proneural gene expression regulates dorsal midbrain neurogenesis.
MedLine Citation:
PMID:  21172336     Owner:  NLM     Status:  In-Data-Review    
Abstract/OtherAbstract:
The balanced proliferation and cell cycle exit of neural progenitors, by generating the appropriate amount of postmitotic progeny at the correct time and in the proper location, is required for the establishment of the highly ordered structure of the adult brain. Little is known about the extrinsic signals regulating these processes, particularly in the midbrain. Fibroblast growth factor (Fgf) 15, the mouse ortholog of FGF19 and member of an atypical Fgf subfamily, is prominently expressed in the dorsolateral midbrain of the midgestational mouse embryo. In the absence of Fgf15, dorsal midbrain neural progenitors fail to exit the cell cycle and to generate the proper amount of postmitotic neurons. We show here that this is due to the altered expression of inhibitory/neurogenic and proneural/neuronal differentiation helix-loop-helix transcription factor (TF) genes. The expression of Id1, Id3, and Hes5 was strongly increased and ectopically expanded, whereas the expression of Ascl1 (Mash1), Neurog1 (Ngn1) and Neurog2 (Ngn2) was strongly decreased and transcription of Neurod1 (NeuroD) was completely abolished in the dorsolateral midbrain of Fgf15(-/-) mice. These abnormalities were not caused by the mis-expression of cell cycle regulatory proteins such as cyclin-dependent kinase inhibitors or retinoblastoma proteins. Furthermore, human FGF19 promotes cell cycle exit of murine dorsal neural progenitors in vitro. Therefore, our data suggest that Fgf15 is a crucial signaling molecule regulating the postmitotic transition of dorsal neural progenitors and thus the initiation and proper progression of dorsal midbrain neurogenesis in the mouse, by controlling the expression of neurogenic and proneural TFs.
Authors:
Thomas Fischer; Theresa Faus-Kessler; Gerhard Welzl; Antonio Simeone; Wolfgang Wurst; Nilima Prakash
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Publication Detail:
Type:  Journal Article     Date:  2010-12-21
Journal Detail:
Title:  Developmental biology     Volume:  350     ISSN:  1095-564X     ISO Abbreviation:  Dev. Biol.     Publication Date:  2011 Feb 
Date Detail:
Created Date:  2011-01-31     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0372762     Medline TA:  Dev Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  496-510     Citation Subset:  IM    
Copyright Information:
Copyright © 2010 Elsevier Inc. All rights reserved.
Affiliation:
Institute of Developmental Genetics, Helmholtz Centre Munich, German Research Centre for Environmental Health (GmbH), and Technical University Munich, Ingolstaedter Landstr. 1, 85764 Neuherberg, Germany.
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