Cell-Autonomous Repression of Shh by Transcription Factor Pax6 Regulates Diencephalic Patterning by Controlling the Central Diencephalic Organizer

• Published in: Cell reports (Cambridge) 2014-09, Vol.8 (5), p.1405-1418
• Main Authors: Caballero, Isabel Martín, Manuel, Martine N., Molinek, Michael, Quintana-Urzainqui, Idoia, Mi, Da, Shimogori, Tomomi, Price, David J.
• Format: Article
• Language: English
• Subjects: Animals; Diencephalon - cytology; Diencephalon - embryology; Diencephalon - metabolism; Eye Proteins - genetics; Eye Proteins - metabolism; Gene Expression Regulation, Developmental; Hedgehog Proteins - genetics; Hedgehog Proteins - metabolism; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Mice; Neurogenesis; Paired Box Transcription Factors - genetics; Paired Box Transcription Factors - metabolism; PAX6 Transcription Factor; Promoter Regions, Genetic; Protein Binding; Repressor Proteins - genetics; Repressor Proteins - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2014.07.051

During development, region-specific patterns of regulatory gene expression are controlled by signaling centers that release morphogens providing positional information to surrounding cells. Regulation of signaling centers themselves is therefore critical. The size and the influence of a Shh-producing forebrain organizer, the zona limitans intrathalamica (ZLI), are limited by Pax6. By studying mouse chimeras, we find that Pax6 acts cell autonomously to block Shh expression in cells around the ZLI. Immunoprecipitation and luciferase assays indicate that Pax6 can bind the Shh promoter and repress its function. An analysis of chimeras suggests that many of the regional gene expression pattern defects that occur in Pax6−/− diencephalic cells result from a non-cell-autonomous position-dependent defect of local intercellular signaling. Blocking Shh signaling in Pax6−/− mutants reverses major diencephalic patterning defects. We conclude that Pax6’s cell-autonomous repression of Shh expression around the ZLI is critical for many aspects of normal diencephalic patterning. [Display omitted] •Pax6 limits the effects of a forebrain organizer, the zona limitans intrathalamica•Pax6 blocks diencephalic Shh expression cell autonomously•Absence of Pax6 causes non-cell-autonomous diencephalic patterning defects•Blocking Shh signaling in Pax6−/− mutants reverses diencephalic patterning defects The acquisition of specific features by different regions of the brain is controlled by signaling centers, or organizers, that release morphogens providing information to surrounding cells. The regulation of signaling centers themselves is therefore critical. Caballero et al. find that the size and the influence of a Shh-producing forebrain organizer, the zona limitans intrathalamica, are limited by Pax6, which acts cell autonomously to block Shh expression in surrounding cells. Loss of Pax6 causes expansion of Shh expression that, in turn, causes regional misspecification.