Spindle-derived NT3 in sensorimotor connections: principal role at later stages.

Editor's Note: These short, critical reviews of recent papers in the Journal, written exclusively by graduate students or postdoctoral fellows, are intended to summarize the important findings of the paper and provide additional insight and commentary. For more information on the format and purpose of the Journal Club, please see The circuit between muscle spindles, a subtype of proprioceptors (Ia afferents), and motor neurons is established during late embryonic development and is essential for proper coordination and movement. Muscle spindles, the specialized sensory structures that respond to muscle stretch, are induced by sensory axon innervation around embryonic day 15. As connections between propriocep-tive neurons and muscle spindles are being formed in the periphery, central af-ferents of these neurons are completing the final axonal extension toward the ven-tral spinal cord, where they will form connections with motor neurons. Some evidence suggests that muscle spindles produce signals that influence the establishment of functional central connections (for review, see Chen et al., 2003). One spindle-derived signal that might be responsible for development of sensorimo-tor connections is neurotrophin-3 (NT3). NT3 induces sensory neuron expression of ER81, a transcription factor that controls the extension of the central sensory projections toward the ventral spinal cord. Indeed, in NT3/Bax double-knockout mice, in which the neuronal cell death due to NT3 absence is prevented by deleting the proapoptotic protein Bax, the afferent axons do not extend beyond the intermediate spinal cord, a phenotype similar to that of mice lacking ER81 (Ar-ber et al., 2000; Patel et al., 2003). Muscle spindles are either abnormal or absent in both of these mutants. In contrast to these results, central connections appear to project normally to ventral spinal cord in other mouse models , despite severely compromised development of muscle spindles. For example, no gross defects in central projections were observed in Neuregulin 1 knockout mice, in which muscle spindles were not induced (Hippenmeyer et al., 2002). Similarly , central projections in mice lacking the Neuregulin 1 receptor ErbB2 in muscles appear to project normally to ventral cord, even though muscle spindles in these mice are immature and greatly reduced in number (Leu et al., 2003). On the other hand, the presence of grossly normal Ia afferent projection patterns in the spinal cord does not necessarily mean that sensorimotor connections are functional. Indeed, monosynaptic responses are greatly reduced postnatally in Egr3-null mice, in which central projections extend to ven-tral spinal cord, but …