INTRODUCTION OF A NEUROTROPHIN-3 TRANSGENE INTO MUSCLE SELECTIVELY RESCUES PROPRIOCEPTIVE NEURONS IN MICE LACKING ENDOGENOUS NEUROTROPHIN-3

To clarify the role of muscle-derived neurotrophin-3 (NT-3) in the dev elopment of sensory neurons, we generated transgenic mice selectively overexpressing NT-3 in skeletal muscles under the control of a myogeni n promoter (myo-NT-3 mice). The myo-NT-3 transgene was then bred into an NT-3 null mutant (-/-) line to generate myo-NT-3, NT-3(-/-) mice in which NT-3 was expressed in muscles, but not elsewhere. Transient ove rexpression of NT-3 in developing muscles increased the number of prop rioceptive neurons as well as the density of both their central and pe ripheral projections, resulting in more la afferents in spinal cord an d more spindles (end organs of la afferents) in muscles. NT-3 expressi on restricted to muscles was sufficient to secure the development of p roprioceptive neurons and their central and peripheral projections in myo-NT-3, NT-3(-/-) mice. The loss of nonproprioceptive neurons observ ed in NT-3(-/-) mice was not reversed by the transgene, suggesting tha t these neurons are regulated by NT-3 from sources other than muscle. We conclude that target-derived rather than intraganglionic NT-3 is pr eeminent in supporting the development of proprioceptive neurons. The level of NT-3 in developing muscles may be the principal factor determ ining the number of proprioceptive neurons in dorsal root ganglions an d spindles in skeletal muscles of adults.