onetheless, collectively, these findings indi cate divergence with the signaling underlying the inductive and orienting responses of dI neurons to BMP7. Type I BMP receptor kinase activity is just not expected for the chemotropic activity of BMP7, posing the ques tion of how an axon orienting signal is generated. Three lines of evidence recommend that stimulation of PI3K activ ity represents a pathway chosen by BMP7 to evoke axonal orientation and supply further help to the model for independence of BMP7 signaling pathways. Initial, in the low concentrations at which BMP7 stimu lates growth cone collapse in dI neurons, PI3K depen dent signaling, but not Smad1 five 8 phosphorylation, is activated by BMP7. Second, BMP6 will not stimulate PI3K dependent Akt activity in dI neurons at any con centration tested, paralleling its lack of orienting ability.
selleck inhibitor Third, the blockade by LY and WM of BMP7 evoked development cone collapse and orientation of spinal axons, but not of BMP evoked neuronal specification, suggests the involvement of PI3K as a signaling element selec tive for the orienting activity of BMP7. Similar benefits were obtained with two distinct inhibitors, supporting the view that PI3K was the target and is usually a mediator in this pathway. PI3K is known to be an intermediate in pathways that regulate cell motility and migration, raising the possibility that indiscriminate block ade of growth cone cytoskeletal dynamics underlies the block of BMP7 evoked axon orientation. Against this argument, Netrin 1 evoked axon orientation was unaf fected by blockade of PI3K activity, indicating selectivity with the BMP7 evoked pathway for axon orientation.
Several intracellular discover this mediators, PI3K, LIMK and Rho GTPases, have been implicated in BMP evoked chemo taxis, growth cone and axon orientation and also the dynamics of axon extension. How do these connected signals conspire to elicit BMP dependent cytoskeletal reorganization Our final results add to the growing proof for a BMP evoked chemotro pic signaling pathway that contains PI3K, most likely activated by sort II BMP receptors. Through the action of down stream pathway elements, which include Rho GTPases, PI3K activation may perhaps lead to oriented regulation of cytos keletal dynamics. BMP activated LIMK, in portion nership with cofilin, may perhaps act in parallel to regulate the price of response to the chemorepellent BMP7.
Nonetheless, facts with the interactions and hierarchies in this pathway stay to become determined. The origins of BMP7 signaling divergence The issue of how morphogens elicit both inductive and tropic actions has not too long ago been addressed for Wnt and Hh proteins. In these instances, regulation of intracellular responses appears to depend on differen tial expression and activation of canonical and distinct, non canonical, receptors and co receptors, while so far in separate cells. In a departure from this theme, BMPs appear to activate variously grouped subsets of a somewhat small collection of canonical BMP receptors to elicit differential responses, which, importantly, can happen in an indi vidual cell.