Dependence of developing group Ia afferents on neurotrophin-3

At birth, group Ia proprioceptive afferents and muscle spindles, whose formation is Ia afferent-dependent, are absent in mice carrying a deletion in the gene for neurotrophin-3 (NT-3-/-). Whether Ia afferents contact myotubes, resulting in the formation of spindles which subsequently degenerate, or whether Ia afferents and spindles never form was examined in NT-3-/- mice at embryonic days (E) 10.5-18.5 by light and electron microscopy. Three sets of data indicate that Ia neurons do not develop and spindles do not form in NT-3-deficient mice. First, peripheral projections of Ia afferents did not innervate hindlimbs of NT-3-/- mice, as reflected by a deficiency of nerve fibers in limb peripheral nerves and an absence of afferent nerve-muscle contacts and spindles in the soleus muscle at E13.5-E18.5. Second, central projections of Ia afferents did not innervate the spinal cord in the absence of NT-3, as shown by an atrophy of the dorsal spinal roots and absence of afferent projections from limb musculature to spinal motor neurons at E13.5 or E15.5. Lastly, the lumbar dorsal root ganglia (DRGs) at E10.5-E14.5, the stages of development that precede or coincide with the innervation of the spinal cord and hindlimbs by Ia afferents, were 20-64% smaller in mutant than in wild-type mice, presumably because the cell bodies of Ia neurons were absent in embryos lacking NT-3. The failure of Ia neurons to differentiate and/or survive and Ia afferent projections to form in early fetal mice lacking NT-3 suggests that NT-3 may regulate neuronal numbers by mechanisms operating prior to neurite outgrowth to target innervation fields. Thus, developing Ia neurons may be dependent on NT-3 intrinsic to the DRGs before they reach a stage of potential dependence on NT-3 retrogradely derived from skeletal muscles or spinal motor neurons.