A Role for BMP Heterodimers in Roof Plate-Mediated Repulsion of Commissural Axons

Abstract

During spinal cord development, commissural neurons extend their axons ventrally, away from the roof plate. The roof plate is the source of a diffusible repellent that orients commissural axons in vitro and, thus, may regulate the trajectory of commissural axons in vivo. Of three Bmps expressed in the roof plate, BMP7, but not BMP6 or GDF7, mimics the roof plate activity in vitro. We show here that expression of both Bmp7 and Gdf7 by roof plate cells is required for the fidelity of commissural axon growth in vivo. We also demonstrate that BMP7 and GDF7 heterodimerize in vitro and that, under these conditions, GDF7 enhances the axon-orienting activity of BMP7. Our findings suggest that a GDF7:BMP7 heterodimer functions as a roof plate-derived repellent that establishes the initial ventral trajectory of commissural axons.

c-Jun N-terminal Kinase 1 (JNK1) Is Required for Coordination of Netrin Signaling in Axon Guidance

“…Wnt4 guides post-crossing commissural axons along the anterior-posterior axis of the spinal cord (58). Bone morphogenetic proteins function as chemorepellents involved in initial guidance of commissural axons (59,60). It remains to be determined whether JNK activation is involved in the downstream signaling pathway of these guidance cues.…”

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

“…BMP signals induce interneuron populations in the dorsal (dI1-dI3), but not more ventral (dI4-dI6) spinal cord (Liem et al 1995(Liem et al , 1997. Addition of BMP-4, BMP-6, BMP-7, or GDF-7 to naïve caudal neural plate explants mimics roof-plate-mediated induction of dI1 and dI3 interneurons (Liem et al 1997;Lee et al 1998;Butler and Dodd 2003), and complete ablation of the roof plate results in failure to form dI1-dI3 interneurons leading to expansion of dI4-dI6 interneurons (Lee et al 2000). Deletion of both BMPRIA and BMPRIB from the dorsal spinal cord leads to a complete loss of the dorsal-most dI1 interneurons (Wine- Lee et al 2004), whereas activation of BMPRIA and BMPRIB expands dI1 interneurons at the expense of other interneuron types (Timmer et al 2002;Chizhikov and Millen 2004a;Liu et al 2004).…”

“…BMPs act as inductive signals to promote growth cone guidance, axonal orientation and path finding. During spinal cord development, BMP-6, BMP-7, and GDF-7 are expressed in the rodent roof plate and direct commissural neuron axon extension through the spinal cord toward the floor plate (Lee et al 1998;Augsburger et al 1999;Butler and Dodd 2003). Explant cultures treated with BMP-7 mimic the repellent activity of the roof plate for commissural axons and directly act to collapse their growth cones (Augsburger et al 1999), whereas Bmp7 2/2 and Gdf7 2/2 explant cultures show very little repellent activity in vitro.…”

“…Explant cultures treated with BMP-7 mimic the repellent activity of the roof plate for commissural axons and directly act to collapse their growth cones (Augsburger et al 1999), whereas Bmp7 2/2 and Gdf7 2/2 explant cultures show very little repellent activity in vitro. Studies show that BMP-7 and GDF-7 form a heterodimer and act cooperatively in vivo for the guidance of commissural axons (Butler and Dodd 2003). Interestingly, BMP-6 and BMP-7 both induce differentiation of commissural neurons, but only BMP-7 is necessary to orient axons Dodd 2011, 2012).…”

Protein Kinase A Regulates the Sensitivity of Spinal Commissural Axon Turning to Netrin-1 But Does Not Switch between Chemoattraction and Chemorepulsion

“…Together, these findings have led to a model in which cAMP and protein kinase A (PKA) are downstream effectors of netrin-1 signaling, while also regulating the directionality of the axonal response to netrin-1 (Hopker et al, 1999;Song and Poo, 1999;Shewan et al, 2002;Nishiyama et al, 2003) We tested this model of netrin-1 chemotropic function using embryonic rat spinal commissural neurons, cells that extend an axon to the floor plate at the ventral midline of the developing spinal cord. These axons are initially repelled by bone morphogenetic protein-7 (BMP7) and growth/differentiation factor-7 secreted by the roof plate at the dorsal midline (Augsburger et al, 1999;Butler and Dodd, 2003) and then attracted by netrin-1 and sonic hedgehog secreted by the floor plate Serafini et al, 1994;Charron et al, 2003). We reported previously that activating PKA recruits deleted in colorectal cancer (DCC) to the cell surface from an intracellular pool, enhancing axon extension in response to netrin-1 (Bouchard et al, 2004).…”