HUMAN METALLOPROTEASE-DISINTEGRIN KUZBANIAN REGULATES SYMPATHOADRENALCELL FATE IN DEVELOPMENT AND NEOPLASIA

The development of the sympathetic nervous system involves cell-cell i nteractions that regulate the fate and migration of progenitor neural cells. Recent evidence shows that focal membrane-bound protease activi ty is critical for such interactions. The Drosophila kuzbanian (kuz) g ene is required in neurogenesis and encodes a highly conserved, membra ne-bound metalloprotease-disintegrin closley related to the TNF-alpha converting enzyme (TACE). We have characterized the human and mouse ku z homologs and mapped human kuz to chromosome 15q22. During mouse embr yonic development Kuz is expressed mainly in the sympathoadrenal and o lfactory neural precursors. Once sympathoadrenal cells differentiate i nto chromaffin cells in the adult adrenal medulla, they no longer expr ess Kuz. However, we found that tumors of sympathoadrenal origin, such as pheochromocytomas and neuroblastomas, overexpress Kuz. Further, tr ansfection of a kuz construct lacking the protease domain, but not the full-length construct, induces neurite formation in PC12 chromaffin t umor cells. Taken together our results suggest a critical role for Kuz in regulation of sympathoadrenal cell fate.