title: Neural-specific Sox2 input and differential Gli-binding affinity provide context and positional information in Shh-directed neural patterning.
abstract: In the vertebrate neural tube, regional Sonic hedgehog (Shh) signaling invokes a time- and concentration-dependent induction of six different cell populations mediated through Gli transcriptional regulators. Elsewhere in the embryo, Shh/Gli responses invoke different tissue-appropriate regulatory programs. A genome-scale analysis of DNA binding by Gli1 and Sox2, a pan-neural determinant, identified a set of shared regulatory regions associated with key factors central to cell fate determination and neural tube patterning. Functional analysis in transgenic mice validates core enhancers for each of these factors and demonstrates the dual requirement for Gli1 and Sox2 inputs for neural enhancer activity. Furthermore, through an unbiased determination of Gli-binding site preferences and analysis of binding site variants in the developing mammalian CNS, we demonstrate that differential Gli-binding affinity underlies threshold-level activator responses to Shh input. In summary, our results highlight Sox2 input as a context-specific determinant of the neural-specific Shh response and differential Gli-binding site affinity as an important cis-regulatory property critical for interpreting Shh morphogen action in the mammalian neural tube.
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Peterson
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Nishi
authors.forename: Wenxiu
authors.initials: W
authors.lastname: Ma
authors.forename: Anastasia
authors.initials: A
authors.lastname: Vedenko
authors.forename: Leila
authors.initials: L
authors.lastname: Shokri
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Zhang
authors.forename: Matthew
authors.initials: M
authors.lastname: McFarlane
authors.forename: José-Manuel
authors.initials: JM
authors.lastname: Baizabal
authors.forename: Jan Philipp
authors.initials: JP
authors.lastname: Junker
authors.forename: Alexander
authors.initials: A
authors.lastname: van Oudenaarden
authors.forename: Tarjei
authors.initials: T
authors.lastname: Mikkelsen
authors.forename: Bradley E
authors.initials: BE
authors.lastname: Bernstein
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Bailey
authors.forename: Martha L
authors.initials: ML
authors.lastname: Bulyk
authors.forename: Wing H
authors.initials: WH
authors.lastname: Wong
authors.forename: Andrew P
authors.initials: AP
authors.lastname: McMahon
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000235:genetics / Q000502:physiology*; D053823:Hedgehog Proteins / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D054259:Neural Tube / Q000196:embryology / Q000378:metabolism; D011485:Protein Binding; D055748:SOXB1 Transcription Factors / Q000378:metabolism*; 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; C527783:Sox2 protein, mouse; D000071676:Zinc Finger Protein GLI1