Structural distinctions in BMPs underlie divergent signaling in spinal neurons

We demonstrate that whereas all BMPs can induce dorsal neurons, there is selectivity in the ability also to orient axons or evoke growth cone collapse. The degree to which a BMP orients is not predictable by overall protein similarity with other BMPs but comparison of sequences of potent and weakly orienting BMPs with that of the non-orienting BMP6 revealed three candidate positions within the BMPs at which the amino acid residues may confer or obstruct orienting ability. Residue swapping analysis has identified one residue, Gln48 in BMP6, that blocks axon orienting ability. Replacing Gln48 with any of the amino acids present at the equivalent residue position in the orienting subset of BMPs confers orienting activity on BMP6. Conversely, swapping Gln48 into BMP7 reduces orienting ability. The inductive capacity of the BMPs was unchanged by these residue swaps.The results suggest that the presence of the Gln48 residue in BMP6 is structurally inhibitory for BMP/BMPR interactions that result in the activation of intracellular signaling, leading to axon orientation. Moreover, since residue 48 in BMP7 and the corresponding residue in BMP2 are important for type II BMPR binding, our results provide a basis for a mechanistic understanding of the diverse activities of BMPs in spinal cord development.Bone morphogenetic proteins (BMPs) represent a class of TFGβ factors with diverse functions in mammals. BMPs evoke transcriptional events leading to cellular differentiation and survival [1,2] but also direct axon guidance and cellular orienting activities through cytoskeletal signaling [3-5]. The large number of BMPs, their differing affinities for an array of heteromeric BMP receptors (BMPRs), and a range of extracellular and intracellular modulators of BMP/BMPR interactions [6,7] suggest that differential expression of these BMP signaling components could produce the many actions of BMPs. However, in neurons and monocytes, a single BMP can simultaneously evoke both transcrip