Inductive specification and axonal orientation of spinal neurons mediated by divergent bone morphogenetic protein signaling pathways

Abstract

BackgroundBone morphogenetic protein (BMP)7 evokes both inductive and axon orienting responses in dorsal interneurons (dI neurons) in the developing spinal cord. These events occur sequentially during the development of spinal neurons but in these and other cell types such inductive and acute chemotactic responses occur concurrently, highlighting the requirement for divergent intracellular signaling. Both type I and type II BMP receptor subtypes have been implicated selectively in orienting responses but it remains unclear how, in a given cell, divergence occurs. We have examined the mechanisms by which disparate BMP7 activities are generated in dorsal spinal neurons.ResultsWe show that widely different threshold concentrations of BMP7 are required to elicit the divergent inductive and axon orienting responses. Type I BMP receptor kinase activity is required for activation of pSmad signaling and induction of dI character by BMP7, a high threshold response. In contrast, neither type I BMP receptor kinase activity nor Smad1/5/8 phosphorylation is involved in the low threshold orienting responses of dI axons to BMP7. Instead, BMP7-evoked axonal repulsion and growth cone collapse are dependent on phosphoinositide-3-kinase (PI3K) activation, plausibly through type II receptor signaling. BMP7 stimulates PI3K-dependent signaling in dI neurons. BMP6, which evokes neural induction but does not have orienting activity, activates Smad signaling but does not stimulate PI3K.ConclusionsDivergent signaling through pSmad-dependent and PI3K-dependent (Smad-independent) mechanisms mediates the inductive and orienting responses of dI neurons to BMP7. A model is proposed whereby selective engagement of BMP receptor subunits underlies choice of signaling pathway.

TGF-β Family Signaling in Neural and Neuronal Differentiation, Development, and Function

“…Interestingly, BMP-6 and BMP-7 both induce differentiation of commissural neurons, but only BMP-7 is necessary to orient axons Dodd 2011, 2012). The fast-acting repellent action of BMP-induced axonal orientation suggests signaling through cytoskeletal actin remodeling and c-Jun amino-terminal kinase (JNK)-mediated microtubule stabilization (Wen et al 2007;Podkowa et al 2010;Perron and Dodd 2011). Additional signaling from activin aids in organizing neural circuitry, and the expression of the activin bA subunit at E17 in the telencephalon indicates a possible role in topographical wiring between the neocortex and neostriatum (Andreasson and Worley 1995).…”

Type Ib BMP receptors mediate the rate of commissural axon extension through inhibition of cofilin activity

“…6J) (Bernard, 2007). The ability of BMPs to re-orient commissural axons appears to be controlled through activation of the phosphoinositide-3-kinase pathway (Perron and Dodd, 2011).…”

From classical to current: Analyzing peripheral nervous system and spinal cord lineage and fate

“…2B, C). dI1 axons are directed ventrally in response to members of the BMP family present in the roof plate here acting as a chemorepellents (Augsburger et al, 1999; Butler and Dodd, 2003; Yamauchi et al, 2008) to both orient and slow the rate of axon growth through the dorsal spinal cord (Perron and Dodd, 2011; Phan and Butler, 2013; Phan et al, 2010; Yamauchi et al, 2013). Tag1 + dI1 axons extend towards the floor plate by taking a circumferential route through the transverse plane of the spinal cord (Fig 2B).…”