title: Activation of Class I transcription factors by low level Sonic hedgehog signaling is mediated by Gli2-dependent and independent mechanisms.
abstract: The partitioning of the ventral neural tube into five distinct neuronal progenitor domains is dependent on the morphogenic action of the secreted protein Sonic hedgehog (Shh). The prevailing model stipulates that Class I genes are repressed and Class II genes are activated by high levels of Shh signaling and that sharp progenitor domain boundaries are established by the mutual repression of complementary pairs of Class I and Class II transcription factors. While core elements of this model are supported by experimental evidence, a number of issues remain unresolved. Foremost of these is a more thorough understanding of the mechanism by which Class I genes are regulated. In this study, we describe the consequences of Shh misexpression on Class I and Class II gene expression in the hindbrain of ShhP1 embryos. We observed that an ectopic source of Shh in the otic vesicle of ShhP1 embryos ventralized the adjacent hindbrain by inducing, rather than repressing, the expression of several Class I genes (Pax6, Dbx1, Dbx2). The Shh dependent activation of Class I genes was mediated, in part, by Gli2. These results bear significance on the model of ventral neural tube patterning as they suggest a dual role for Shh in the regulation of Class I genes, whereby low levels of Shh signaling initiate Class I gene transcription, while higher levels restrict the domains of Class I gene expression to intermediate positions of the neural tube through the activation of Class II transcriptional regulators.
authors.affiliation: Department of Genetics, University of Pennsylvania, School of Medicine, Clinical Research Bldg., Room 470, 415 Curie Blvd., Philadelphia, PA 19104, USA.
authors.forename: Abraham
authors.initials: A
authors.lastname: Pachikara
authors.forename: Diane K
authors.initials: DK
authors.lastname: Dolson
authors.forename: Lenka
authors.initials: L
authors.lastname: Martinu
authors.forename: Martin M
authors.initials: MM
authors.lastname: Riccomagno
authors.forename: Yongsu
authors.initials: Y
authors.lastname: Jeong
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Epstein
mesh_terms: D000818:Animals; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D053823:Hedgehog Proteins / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D012249:Rhombencephalon / Q000196:embryology*; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*; D000075746:Zinc Finger Protein Gli2
chemical_list: C000618551:Gli2 protein, mouse; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D051741:Kruppel-Like Transcription Factors; C465570:Shh protein, mouse; D014157:Transcription Factors; D000075746:Zinc Finger Protein Gli2