Comparison of MSX-1 and MSX-2 suggests a molecular basis for functional redundancy

This study examines the biochemical properties of two members of the murine MSX family, MSX-1 and MSX-2, which have been implicated to have partially overlapping functions during embryogenesis. Our analyses show that MSX-1 and MSX-2 share many features in common including their DNA binding and transcriptional properties. In particular, MSX-1 and MSX-2 interact with a common consensus DNA site, and exhibit similar DNA binding site preferences. However, MSX-2 has a higher apparent affinity for DNA, and the distinction between MSX-1 and MSX-2 resides in their differing sequences N-terminal to the homeodomain. With respect to their transcriptional properties, both MSX-1 and MSX-2 function as repressors and share the distinct property that they do so independently of their consensus DNA binding sites. However, MSX-1 is a more potent repressor, and the difference between these proteins also maps to their N-terminal regions. Similarly, the expression patterns of Msx-1 and Msx-2 as examined by whole mount in situ hybridization are related but not identical. Thus, Msx-1 and Msx-2 are co-expressed in the limbs, neural tube, and branchial arches; however, Msx-1 has a broader expression pattern overall and is expressed uniquely in certain embryonic regions. These features suggest that these members of the Msx family are 'equivalent but not equal' and that their proposed redundancy may be achieved via distinct biochemical mechanisms that yield a similar functional outcome.