title: Mechanistic differences in the transcriptional interpretation of local and long-range Shh morphogen signaling.
abstract: Morphogens orchestrate tissue patterning in a concentration-dependent fashion during vertebrate embryogenesis, yet little is known of how positional information provided by such signals is translated into discrete transcriptional outputs. Here we have identified and characterized cis-regulatory modules (CRMs) of genes operating downstream of graded Shh signaling and bifunctional Gli proteins in neural patterning. Unexpectedly, we find that Gli activators have a noninstructive role in long-range patterning and cooperate with SoxB1 proteins to facilitate a largely concentration-independent mode of gene activation. Instead, the opposing Gli-repressor gradient is interpreted at transcriptional levels, and, together with CRM-specific repressive input of homeodomain proteins, comprises a repressive network that translates graded Shh signaling into regional gene expression patterns. Moreover, local and long-range interpretation of Shh signaling differs with respect to CRM context sensitivity and Gli-activator dependence, and we propose that these differences provide insight into how morphogen function may have mechanistically evolved from an initially binary inductive event.
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden. oosterveen.t@gmail.com
authors.forename: Tony
authors.initials: T
authors.lastname: Oosterveen
authors.forename: Sanja
authors.initials: S
authors.lastname: Kurdija
authors.forename: Zhanna
authors.initials: Z
authors.lastname: Alekseenko
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Uhde
authors.forename: Maria
authors.initials: M
authors.lastname: Bergsland
authors.forename: Magnus
authors.initials: M
authors.lastname: Sandberg
authors.forename: Elisabet
authors.initials: E
authors.lastname: Andersson
authors.forename: José M
authors.initials: JM
authors.lastname: Dias
authors.forename: Jonas
authors.initials: J
authors.lastname: Muhr
authors.forename: Johan
authors.initials: J
authors.lastname: Ericson
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D019521:Body Patterning; D002490:Central Nervous System / Q000196:embryology / Q000378:metabolism; D002642:Chick Embryo; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000235:genetics* / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D055495:Neurogenesis; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D015398:Signal Transduction; D000071676:Zinc Finger Protein GLI1
chemical_list: C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D055748:SOXB1 Transcription Factors; C465570:Shh protein, mouse; D000071676:Zinc Finger Protein GLI1