Circuit Formation in the Spinal Cord

The direction of growth chosen by axons from different neuron classes must be exquisitely regulated to ensure proper connectivity within spinal cord circuits. Thus motor neurons, whose axons are the earliest to grow out of the spinal cord, are directed to an exit point lateral and anterior, based on chemoattractant signals that guide them there and cell surface adhesion molecules that facilitate their exit from the central nervous system. Additional cell adhesion molecules maintain the appropriate trajectory for these axons and facilitate the formation of a coherent nerve. Chemorepulsive signals prevent axons from growing aberrantly to inappropriate nonmuscle targets. Accordingly, motor axons grow to their skeletal muscle and autonomic ganglia targets with great fidelity.

The parallel growth of several classes of sensory neuron axons within the spinal cord illustrates the complexity—and remarkable precision—of the relationship between cell position, axon guidance, and molecular signals that attract or repel subsets of axons. Sensory relay neurons or interneurons generated from the alar plate either extend axons across the anterior midline and then into the spinothalamic tract or into the motor column on the same side to make local reflex connections (like those necessary for withdrawal in response to painful stimuli). Clearly, there need to be discriminating sets of signals: one set that attracts spinothalamic relay axons to the anterior midline and then maintains them on the contralateral side, and one set that attracts interneuron axons to the anterior horn and prevents them from extending past the midline. The signals that influence the commissural axons are now fairly well understood. These include a secreted chemoattractant molecule called netrin, which is similar in its molecular structure to the extracellular matrix adhesion molecule laminin, and a secreted chemorepulsive molecule called slit, which signals an axon that it should not cross back once it has crossed the midline. Thus the anatomic precision of pathways for relaying pain and temperature is generated by precise molecular mechanisms that attract axons to the midline, guide them across, and then maintain them on the contralateral side of the spinal cord, brainstem, thalamus, and cortex.

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