title: Ongoing sonic hedgehog signaling is required for dorsal midline formation in the developing forebrain.
abstract: The division of the mammalian forebrain into distinct left and right hemispheres represents a critical step in neural development. Several signaling molecules including sonic hedgehog (SHH), fibroblast growth factor 8 (FGF8), and bone morphogenetic proteins (BMPs) have been implicated in dorsal midline development, and prior work suggests that the organizing centers from which these proteins are secreted mutually regulate one another during development. To explore the role of the ventral organizing center in the formation of two hemispheres, we assessed dorsal midline development in Shh mutant embryos and in wildtype embryos treated with the SHH signaling inhibitor HhAntag. Collectively, our findings demonstrate that SHH signaling plays an important role in maintaining the normal expression patterns of Fgf8 and Bmp4 in the developing forebrain. We further show that FGF8 can induce the expression of Zic2, which is normally expressed at the midline and is required in vivo for hemispheric cleavage, suggesting that FGF signaling may stimulate dorsal midline development by inducing Zic2 expression.
authors.affiliation: Department of Biological Sciences, Stanford University, Stanford, CA 94305, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Hayhurst
authors.forename: Bryan B
authors.initials: BB
authors.lastname: Gore
authors.forename: Marc
authors.initials: M
authors.lastname: Tessier-Lavigne
authors.forename: Susan K
authors.initials: SK
authors.lastname: McConnell
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000235:genetics; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D001973:Bromodeoxyuridine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000502:physiology*; D004627:Embryonic Induction / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051524:Fibroblast Growth Factor 8 / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D016142:Holoprosencephaly / Q000235:genetics; D020287:In Situ Nick-End Labeling / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009924:Organ Culture Techniques; D016548:Prosencephalon / Q000196:embryology* / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D004791:Enzyme Inhibitors; D053823:Hedgehog Proteins; C465570:Shh protein, mouse; D014157:Transcription Factors; C491811:Zic2 protein, mouse; D051524:Fibroblast Growth Factor 8; D001973:Bromodeoxyuridine