title: Evidence that FGF8 signalling from the midbrain-hindbrain junction regulates growth and polarity in the developing midbrain.
abstract: The developing vertebrate mesencephalon shows a rostrocaudal gradient in the expression of a number of molecular markers and in the cytoarchitectonic differentiation of the tectum, where cells cease proliferating and differentiate in a rostral to caudal progression. Tissue grafting experiments have implicated cell signalling by the mesencephalic-metencephalic (mid-hindbrain) junction (or isthmus) in orchestrating these events. We have explored the role of Wnt-1 and FGF8 signalling in the regulation of mesencephalic polarity. Wnt-1 is expressed in the caudal mesencephalon and Fgf8 in the most rostral metencephalon. Wnt-1 regulates Fgf8 expression in the adjacent metencephalon, most likely via a secondary mesencephalic signal. Ectopic expression of Fgf8 in the mesencephalon is sufficient to activate expression of Engrailed-2 (En-2) and ELF-1, two genes normally expressed in a decreasing caudal to rostral gradient in the posterior mesencephalon. Ectopic expression of Engrailed-1 (En-1), a functionally equivalent homologue of En-2 is sufficient to activate ELF-1 expression by itself. These results indicate the existence of a molecular hierarchy in which FGF8 signalling establishes the graded expression of En-2 within the tectum. This in turn may act to specify other aspects of A-P polarity such as graded ELF-1 expression. Our studies also reveal that FGF8 is a potent mitogen within the mesencephalon: when ectopically expressed, neural precursors continue to proliferate and neurogenesis is prevented. Taken together our results suggest that FGF8 signalling from the isthmus has a key role in coordinately regulating growth and polarity in the developing mesencephalon.
authors.affiliation: Department of Molecular and Cellular Biology, The Biolabs, Harvard University, Cambridge, MA 02138, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Lee
authors.forename: P S
authors.initials: PS
authors.lastname: Danielian
authors.forename: B
authors.initials: B
authors.lastname: Fritzsch
authors.forename: A P
authors.initials: AP
authors.lastname: McMahon
mesh_terms: D000818:Animals; D019521:Body Patterning; D001921:Brain / Q000196:embryology*; D004268:DNA-Binding Proteins / Q000235:genetics; D004027:Diencephalon / Q000196:embryology; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors; D006133:Growth Substances / Q000235:genetics / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics; D008636:Mesencephalon / Q000196:embryology; D051379:Mice; D008822:Mice, Transgenic; D016296:Mutagenesis; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins; D010641:Phenotype; D011149:Pons / Q000196:embryology; D011518:Proto-Oncogene Proteins / Q000235:genetics; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics; D051153:Wnt Proteins; D051155:Wnt1 Protein; D029961:Zebrafish Proteins; D000099266:Engrailed 2 Protein
chemical_list: D004268:DNA-Binding Proteins; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors; D006133:Growth Substances; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D051153:Wnt Proteins; D051155:Wnt1 Protein; D029961:Zebrafish Proteins; D000099266:Engrailed 2 Protein; C512897:ELF1 protein, human; C512896:Elf1 protein, mouse; C080330:En1 protein, mouse; C496457:Fgf8 protein, mouse; C495246:Wnt1 protein, mouse