Mechanistic Differences in the Transcriptional Interpretation of Local and Long-Range Shh Morphogen Signaling

• DOI: 10.1016/j.devcel.2012.09.015
• Publication Date: 2012-11-12T16:47:50Z
• Authors: Tony Oosterveen; Sanja Kurdija; Zhanna Alekseenko; Christopher W. Uhde; Maria Bergsland; Magnus Sandberg; Elisabet Andersson; José M. Dias; Jonas Muhr; Johan Ericson
• Keywords: Central Nervous System; 0303 health sciences; Neurogenesis; SOXB1 Transcription Factors; Kruppel-Like Transcription Factors; Gene Expression Regulation, Developmental; Chick Embryo; Zinc Finger Protein GLI1; Animals, Genetically Modified; Mice; 03 medical and health sciences; Animals; Hedgehog Proteins; Developmental Biology; Body Patterning; Signal Transduction

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.