PRENATAL AND POSTNATAL REQUIREMENTS OF NT-3 FOR SYMPATHETIC NEUROBLAST SURVIVAL AND INNERVATION OF SPECIFIC TARGETS

Postnatal homozygous neurotrophin-3 mutant mice display a loss of abou t half the sympathetic superior cervical ganglion (SCG) neurons (Ernfo rs, P., Lee, K.-F., Kucera, J. and Jaenisch, R. (1994a) Cell 77, 503-5 12; Farinas, I., Jones, K. R., Backus, C., Wang, X. Y. and Reichardt, L. F. (1994) Nature 369, 658-661), We found that this loss is caused b y excessive apoptosis of sympathetic neuroblasts leading to a failure to generate a normal number of neurons during neurogenesis, NT-3 was a lso found to be required postnatally. In Nt-3(-/-) mice, sympathetic f ibers failed to invade pineal gland and external ear postnatally; wher eas other targets of the external and internal carotid nerves, includi ng the submandibular gland and the iris, displayed a normal complement of sympathetic innervation, Sympathetic fibers of mice carrying one f unctional copy of the Nt-3 gene (Nt-3(+/-) mice) invaded the pineal gl and, but failed to branch and form a ground plexus. Cultured neonatal sympathetic neurons responded to NT-3 by neurite outgrowth and mRNA up regulation of the NT-3 receptor, trkC. Exogenously administered NT-3 p romoted sympathetic growth and rescued the sympathetic target deficit of the mutant mice, We conclude that NT-3 is required for the survival of sympathetic neuroblasts during neurogenesis and for sympathetic in nervation and branching in specific targets after birth.