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Dev Cell. 2012 Nov 13;23(5):1006-19. doi: 10.1016/j.devcel.2012.09.015.

Mechanistic differences in the transcriptional interpretation of local and long-range Shh morphogen signaling.

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Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden.


Morphogens orchestrate tissue patterning inĀ 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 facilitateĀ 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.

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