Npn-1 Contributes to Axon-Axon Interactions That Differentially Control Sensory

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Npn-1 Contributes to Axon-Axon Interactions That Differentially Control Sensory

and Motor Innervation of the Limb

http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1001020

References

-Eva Huettl1#, Heidi Soellner1#, Bianchi1, G. Novitch2,

B. Huber1*

1 Institute of Developmental Genetics, Helmholtz Zentrum München–German Research

Center for Environmental Health, Neuherberg, Germany, 2 Department of

Neurobiology, Broad Center of Regenerative Medicine and Stem Cell Research,

Geffen School of Medicine at UCLA, Los Angeles, California, United States

of America

Abstract

The initiation, execution, and completion of complex locomotor behaviors are

depending on precisely integrated neural circuitries consisting of motor

pathways that activate muscles in the extremities and sensory afferents that

deliver feedback to motoneurons. These projections form in tight temporal and

spatial vicinities during development, yet the molecular mechanisms and cues

coordinating these processes are not well understood. Using cell-type specific

ablation of the axon guidance receptor Neuropilin-1 (Npn-1) in spinal

motoneurons or in sensory neurons in the dorsal root ganglia (DRG), we have

explored the contribution of this signaling pathway to correct innervation of

the limb. We show that Npn-1 controls the fasciculation of both projections and

mediates inter-axonal communication. Removal of Npn-1 from sensory neurons

results in defasciculation of sensory axons and, surprisingly, also of motor

axons.

In addition, the tight coupling between these two heterotypic axonal populations

is lifted with sensory fibers now leading the spinal nerve projection. These

findings are corroborated by partial genetic elimination of sensory neurons,

which causes defasciculation of motor projections to the limb.

Deletion of Npn-1 from motoneurons leads to severe defasciculation of motor

axons in the distal limb and dorsal-ventral pathfinding errors, while outgrowth

and fasciculation of sensory trajectories into the limb remain unaffected.

Genetic elimination of motoneurons, however, revealed that sensory axons need

only minimal scaffolding by motor axons to establish their projections in the

distal limb. Thus, motor and sensory axons are mutually dependent on each other

for the generation of their trajectories and interact in part through

Npn-1-mediated fasciculation before and within the plexus region of the limbs.

Author Summary

During embryonic development, growing axons establish intricate neural networks

with their peripheral targets, a process that builds the basis for complex

behaviors. While wiring up the proper circuits in peripheral limbs, for example,

motor axons from the spinal cord and sensory axons from the dorsal root ganglia

converge in the spinal nerve. Here, they intermingle and are subsequently sorted

before reaching the plexus region, the pivotal dorsal-ventral choice point on

their path to the limb.

In this study, we analyzed the contribution of the axon guidance receptor

Neuropilin-1 (Npn-1) to determine how axons choose their path, how well they are

able to maintain their correct path, and how it influences the interactions

between spinal sensory axons and motor axons. We find that when Npn-1 is

eliminated from sensory neurons, both sensory and motor axons are " derailed "

from their correct nerve bundles, and there is a break in the tight coupling

between these axonal populations.

Loss of Npn-1 in motoneurons, however, leads to impairments in axon bundling and

pathfinding errors only in motor axons, while sensory axons remain unaffected.

Genetic ablation studies of either sensory or motor neurons corroborate the

results on the mutual dependency and specificity of the outgrowing spinal

projections.

These results reveal a role for Npn-1 in controlling specific axon-axon

interactions that lead to formation of proper spinal sensory-motor trajectories

to the limb. Furthermore, they suggest that the presence of minimal numbers of

sensory or motor axons is sufficient for the formation of correct spinal

projections.

Citation: Huettl R-E, Soellner H, Bianchi E, Novitch BG, Huber AB (2011) Npn-1

Contributes to Axon-Axon Interactions That Differentially Control Sensory and

Motor Innervation of the Limb. PLoS Biol 9(2): e1001020.

doi:10.1371/journal.pbio.100