title: Fgf15-mediated control of neurogenic and proneural gene expression regulates dorsal midbrain neurogenesis.
abstract: 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.affiliation: Institute of Developmental Genetics, Helmholtz Centre Munich, Technical University Munich, Neuherberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Fischer
authors.forename: Theresa
authors.initials: T
authors.lastname: Faus-Kessler
authors.forename: Gerhard
authors.initials: G
authors.lastname: Welzl
authors.forename: Antonio
authors.initials: A
authors.lastname: Simeone
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wurst
authors.forename: Nilima
authors.initials: N
authors.lastname: Prakash
mesh_terms: D000818:Animals; D002453:Cell Cycle; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D005346:Fibroblast Growth Factors / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D019394:Ki-67 Antigen / Q000032:analysis; D008636:Mesencephalon / Q000196:embryology*; D051379:Mice; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000166:cytology; D055495:Neurogenesis
chemical_list: D019394:Ki-67 Antigen; C498355:Mki67 protein, mouse; C108526:fibroblast growth factor 15, mouse; D005346:Fibroblast Growth Factors