Take two neighboring cells from the same tissue—cells that are about as identical as any could be. Despite their similarities, these two cells could actually vary massively in their transcriptome. The typical fate of an mRNA—the “transcript” in transcriptome—is to serve as a template to make a protein, but it isn’t clear that the differences in mRNA levels directly translate into differences in protein levels—or functional consequences.

In the March issue of G3, Zhang et al. present evidence that Sonic Hedgehog (SHH), a signaling protein crucial for proper limb development, exhibits marked variance for the first 10 hours of limb development in mouse and chick models. SHH concentration in cells is known to be strongly correlated with digit identity, so it might seem more likely that the concentration of the protein would be held steady—the opposite of what Zhang et al. observed. To explain this, they hypothesize that the gradient of SHH, not the absolute concentration, is critical for correct digit patterning in different parts of the growing limb bud. However, the variance in SHH levels may play some other, yet-to-be-determined role in development.

Zhang et al. also found that the variance in SHH levels disappeared after the first 10 hours of limb development. When this loss of variance was suppressed, affected animals developed extra toes that were longer than normal. This suggests that the less variable SHH levels at this later stage of limb development are crucial for correct limb outgrowth.

Altogether, the group’s work implies a potentially important role for variance in development, at least in pathways connected to SHH. And since digit number and length vary among species and may have an impact on fitness, their findings may even reflect a role for SHH variance in evolution: a tiny genetic tweak that alters the timing or patterning of this variance could bring about large, possibly advantageous changes in phenotype.


Zhang, R.; Lee, C.; Lawson, L.; Svete, L.; McIntyre, L.; Harfe, D. SHH Protein Variance in the Limb Bud Is Constrained by Feedback Regulation and Correlates with Altered Digit Patterning.
G3, 7(3), 851-858.
DOI: 10.1534/g3.116.033019

Nicole Haloupek is a freelance science writer and a recent graduate of UC Berkeley's molecular and cell biology PhD program.

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