Thin filaments (red) become elongated when nebulin is lost. Titin (blue) and thick filaments (green) are unaffected.

On page 947, McElhinny et al. suggest that nebulin is a molecular ruler for actin filaments in muscle cells.

Muscle physiology depends on the precise alignment, length, and overlap of thin (actin) and thick (myosin) filaments. Capping proteins such as Tmod stop the growing and shrinking of dynamic thin filaments but lack the innate ability to know when to do so. The new results show that the capping proteins know when to act because of nebulin, a giant protein that spans the length of thin filaments.Nebulin's size varies by muscle cell type, and the variation correlates with thin filament length. McElhinny et al. removed nebulin from cultured heart muscle cells by RNAi and found that the actin filaments became unruly. Their pointed ends (which overlap with thick filaments) were no longer decorated by Tmod and thus grew past their normal lengths. Barbed ends were also disorganized in the absence of nebulin.

As expected, muscle contraction was impaired by the uneven, elongated thin filaments. Muscle development might also depend on thin filament precision, as skeletal myotube maturation was blocked by nebulin RNAi. Alternatively, nebulin might harbor an undiscovered signaling function.

Nebulin was also detected in nonmuscle cells, where it might set the lengths of actin filaments of cilia and microvilli. Some researchers remain skeptical of the ruler theory unless mutant nebulins of various sizes can be shown to dictate filament lengths. Nebulin's large size and modular structure, however, make this a challenging experiment.