Rostral growth of commissural axons requires the cell adhesion molecule MDGA2

Abstract

BackgroundLong-distance axonal growth relies on the precise interplay of guidance cues and cell adhesion molecules. While guidance cues provide positional and directional information for the advancing growth cone, cell adhesion molecules are essential in enabling axonal advancement. Such a dependence on adhesion as well as guidance molecules can be well observed in dorsal commissural interneurons, which follow a highly stereotypical growth and guidance pattern. The mechanisms and molecules involved in the attraction and outgrowth towards the ventral midline, the axon crossing towards the contralateral side, the rostral turning after midline crossing as well as the guidance along the longitudinal axis have been intensely studied. However, little is known about molecules that provide the basis for commissural axon growth along the anterior-posterior axis.ResultsMDGA2, a recently discovered cell adhesion molecule of the IgCAM superfamily, is highly expressed in dorsolaterally located (dI1) spinal interneurons. Functional studies inactivating MDGA2 by RNA interference (RNAi) or function-blocking antibodies demonstrate that either treatment results in a lack of commissural axon growth along the longitudinal axis. Moreover, results from RNAi experiments targeting the contralateral side together with binding studies suggest that homophilic MDGA2 interactions between ipsilaterally projecting axons and post-crossing commissural axons may be the basis of axonal growth along the longitudinal axis.ConclusionsDirected axonal growth of dorsal commissural interneurons requires an elaborate mixture of instructive (guidance) and permissive (outgrowth supporting) molecules. While Wnt and Sonic hedgehog (Shh) signalling pathways have been shown to specify the growth direction of post-crossing commissural axons, our study now provides evidence that homophilic MDGA2 interactions are essential for axonal extension along the longitudinal axis. Interestingly, so far each part of the complex axonal trajectory of commissural axons uses its own set of guidance and growth-promoting molecules, possibly explaining why such a high number of molecules influencing the growth pattern of commissural interneurons has been identified.

A Pooling Genome-Wide Association Study Combining a Pathway Analysis for Typical Sporadic Parkinson’s Disease in the Han Population of Chinese Mainland

“…While Wnt and Sonic hedgehog (Shh) signaling pathways have been shown to specify the growth direction of post-crossing commissural axons, homophilic MDGA2 interactions are essential for axonal extension along the longitudinal axis [25]. The role in neuropathology of dopaminergic neurons has been suggested for reactive astrocytes [26], microglial activation [27], dysfunction in the blood-brain barrier (BBB) transporter system [28][29][30], and infiltration of peripheral immune cells [31].…”

SynCAMs – From axon guidance to neurodevelopmental disorders

“…NgCAM and NrCAM, but not Contactin2, stimulated growth of post-crossing axons along the longitudinal axis of the spinal cord (Fitzli et al, 2000). In addition, a role for another IgSF CAM, MDGA2, in post-crossing commissural axon growth was identified, but it is not known whether MDGA2 binds to either NgCAM or NrCAM (Joset et al, 2011).…”

Wiring the Vascular Network with Neural Cues: A CNS Perspective

“…Note the numerous filopodial extensions emerging from the lamellipodia. The growth cone image is taken from Joset et al (2011), with permission. The scale bar represents 10 mm.…”