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 del etion in the gene for neurotrophin-3 (NT-3 -/-). Whether Ia afferents contact myotubes, resulting in the formation of spindles which subsequ ently 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 n ot develop and spindles do not form in NT-S-deficient mice. First, per ipheral projections of Ia afferents did not innervate hindlimbs of NT- 3 -/- mice, as reflected by a deficiency of nerve fibers in limb perip heral nerves and an absence of afferent nerve-muscle contacts and spin dles 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 a fferent projections from limb musculature to spinal motor neurons at E 13.5 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 inn ervation 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 project ions to form in early fetal mice lacking NT-3 suggests that NT-3 may r egulate neuronal numbers by mechanisms operating prior to neurite outg rowth 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 muscle s or spinal motor neurons. (C) 1995 Wiley-Liss, Inc.