We previously reported that in cocultures of trigeminal or dorsal root ganglia with a variety of peripheral targets (such as whisker pad, forepaw, and heart explants), sensory axons exhibit target specific growth patterns(Ulupinar and Erzurumlu, Soc. Neurosci. Abs., 1997). We are now examining the role of neurotrophins in modulating axon growth patterns and rate. In cocultures of trigeminal or dorsal root ganglia and peripheral explants, the addition of 50 ng/ml NGF to the serum free medium significantly increased the neurite growth density. In contrast, the addition of similar doses of NT-3 caused sensory axons to form only short, complex arbors. Normally E15 primary sensory axons do not grow into E15 heart tissue, but readily grow into younger or older heart explants. High doses of either NGF or NT-3 failed to promote sensory axon entrance into the E15 heart tissue. The upregulation of semaphorins in E15 hearts may account for the failure of exogenous neurotrophins to promote sensory innervation. We therefore, examined the expression of semaphorins in these explant tissues by using RT-PCR primers designed for Murine semaphorins. Our results demonstrate that Sema D is expressed in the E15 heart tissue but not in whisker pad or forepaw explants. The transient expression of Sema D within the developing heart, being expressed at E15 but not at E12 or P1, might explain why primary sensory axons avoid heart tissue only during a brief window in development. Collectively, these results suggest that developing sensory neurons integrate a multitude of positive and negative regulatory signals from the target environment.