Cloning and characterization ofkuzbanian, a gene required for neural development in the fruit fly Drosophila melanogaster

Lateral inhibition is a process commonly employed in the development of higher organisms for the specification of multiple cell types from initially equivalent populations of cells. Many molecular components of the lateral inhibition machinery have been identified in the developing nervous system of Drosophila melanogaster, where signaling through the Notch-Delta pathway governs the selection of single neural precursors from cell equivalence groups known as proneural clusters. However, the mechanism by which lateral inhibition ensures the selection of a single neural precursor is not well understood, and additional essential components of the inhibitory machinery must be isolated and characterized before the process can be fully elucidated.;Using the FLP/FRT system to generate mosaic flies, a novel gene was identified whose multiple sensory bristle phenotype in mutant clones indicated that it is an essential component of the inhibitory signaling that governs the selection of single neural precursors in Drosophila. Flies carrying clones mutant for this gene, called kuzbanian (kuz), exhibited bristle, eye, and wing phenotypes consistent with a requirement for kuz in lateral inhibition. Furthermore, kuz null embryos exhibited extensive neural hyperplasia of the central nervous system, a hallmark of genes of the neurogenic class such as Notch, Delta and shaggy/zw3.;Characterization of the kuz multiple bristle phenotype in mosaic flies revealed that kuz is required in cells with neural potential for them to receive a signal inhibiting the neural fate. These analyses also demonstrated that kuz is necessary for sending a positive signal promoting the neural fate, indicating a dual role for kuz in the specification of the neural cell fate. In addition, the large number of bristles produced in kuz mutant clones suggested that inhibition of a cell's neural potential does not depend upon its direct contact with an emerging neural precursor, a departure from the currently-accepted model of lateral inhibition.;The kuz gene was cloned and its genomic region characterized, revealing multiple alternatively-spliced kuz transcripts. Nucleotide sequence of kuz cDNAs demonstrated that the kuz gene encodes a protein containing metalloprotease and disintegrin domains, and represents a novel member of the ADAM family of proteins.