SONIC HEDGEHOG PROMOTES THE SURVIVAL OF SPECIFIC CNS NEURON POPULATIONS AND PROTECTS THESE CELLS FROM TOXIC INSULT IN-VITRO

Sonic hedgehog (Shh), an axis-determining secreted protein, is express ed during early vertebrate embryogenesis in the notochord and ventral neural tube. In this site it plays a role in the phenotypic specificat ion of ventral neurons along the length of the CNS. For example, Shh i nduces the differentiation of motor neurons in the spinal cord and dop aminergic neurons in the midbrain. Shh expression, however, persists b eyond this induction period, and we have asked whether the protein sho ws novel activities beyond phenotype specification. Using cultures der ived from embryonic day 14.5 (E14.5) rat ventral mesencephalon, we sho w that Shh is also trophic for dopaminergic neurons. Interestingly, Sh h not only promotes dopaminergic neuron survival, but also promotes th e survival of midbrain GABA-immunoreactive (GABA-ir) neurons. In cultu res derived from the E15-16 striatum, Shh promotes the survival of GAB A-ir interneurons to the exclusion of any other cell type. Cultures de rived from E15-16 ventral spinal cord reveal that Shh is again trophic for interneurons, many of which are GABA-ir and some of which express the Lim-1/2 nuclear marker, but it does not appear to support motorne uron survival. Shh does not support the survival of sympathetic or dor sal root ganglion neurons. Finally, using the midbrain cultures, we sh ow that in the presence of MPP+, a highly specific neurotoxin, Shh pre vents dopaminergic neuron death that normally would have occurred. Thu s Shh may have therapeutic value as a protective agent in neurodegener ative disease.