The role of bone morphogenetic protein receptors in commissural axon guidance and growth

2012-04-03A correctly functioning nervous system requires that neural circuits be precisely wired during development. A growing axon must travel through a constantly changing environment, bypassing inappropriate targets to make the correct synapse. To accomplish this feat, axons are directed along the proper path by attractive and repellent cues in the embryonic environment. In addition to directional information, it is critical that axons receive such guidance input at the appropriate time to correctly advance. ❧ Morphogens, signaling molecules that specify cell identity, have been found to also act as axon guidance cues, raising the possibility that the mechanisms that establish neural cell fate are also utilized to assemble neuronal circuits. In the embryonic vertebrate spinal cord, Bone Morphogenetic Proteins (BMPs) initially induce the identity of dorsal interneuron type 1 (dI1) commissural neurons, then subsequently repel their axons – two biologically distinct processes. Specification of cell fate requires nuclear transcription, whereas axon guidance occurs through the rapid reorganization of the cytoskeleton within the growth cone. It remains unresolved, however, how neurons differentially transduce the cell fate specification and guidance activities of morphogens. Do BMPs signal through the same components to accomplish these two diverse functions? ❧ We investigated whether the canonical BMP signaling pathway also mediates axon guidance, and our results suggest that the type I BMP receptors (Bmprs) are responsible for both the morphogenetic and chemorepellent activities of the BMPs in rodent and chick spinal cords. However, while both type I Bmprs, BmprIa and BmprIb, have redundant roles in specifying commissural cell fate, axon guidance is chiefly mediated by only BmprIb. Therefore, the diverse activities of the BMPs are not transduced by different receptor complexes as has been shown for other morphogens. Rather, the canonical receptor complex transduces both activities presumably by the differential activation of the type I Bmprs. Furthermore, we found BmprIb to have an additional role in mediating “temporal” information to commissural axons to specify their rate of growth. Modulation of BmprI activity in commissural neurons indicated BmprIb, and not BmprIa, is required to control the rate of commissural axon outgrowth by regulating the activity of the actin-severing protein cofilin through a non-canonical pathway. Thus, BMPs have the dual function of repelling commissural axons and controlling their rate of outgrowth, such that axons arrive at subsequent guidance points at the correct developmental time