The cryptocephal gene (ATF4) encodes multiple basic-leucine zipper proteins controlling molting and metamorphosis in Drosophila

The cryptocephal (crc) mutation causes pleiotropic defects in ecdysone-regu lated events during Drosophila molting and metamorphosis. Here we report th at crc encodes a Drosophila homolog of vertebrate ATF4, a member of the CRE B/ATF family of basic-leucine zipper (bZIP) transcription factors. We ident ified three putative protein isoforms. CRC-A and CRC-B contain the bZIP dom ain, and CRC-D is a C-terminally truncated form. We have generated seven ne w cre alleles. Consistent with the molecular diversity of crc, these allele s show that crc is a complex genetic locus with two overlapping lethal comp lementation groups. Alleles representing both groups were rescued by a cDNA encoding CRC-B. One lethal group (crc(1), crc(R6), and crc(Rev8)) consists Of strong hypomorphic or null alleles that are associated with mutations o f both CRC-A and CRC-B. These mutants display defects associated with larva l molting and pupariation. In addition, they fail to evert the head and fai l to elongate the imaginal discs during pupation, and they display variable defects in the subsequent differentiation of the adult abdomen. The other group (crc(R1), crc(R2), crc(E85), crc(E98), and crc(929)) is associated wi th disruptions of CRC-A and CRC-D; except for a failure to properly elongat e the leg discs, these mutants initiate metamorphosis normally. Subsequentl y, they display a novel metamorphic phenotype, involving collapse of the he ad and abdomen toward the thorax. The cre gene is expressed throughout deve lopment and in many tissues. In third instar larvae, crc expression is high in targets of ecdysone signaling, such as die leg and wing imaginal discs, and in the ring gland, the source of ecdysone. Together, these findings im plicate CREB/ATF proteins in essential functions during molting and metamor phosis. In addition, the similarities between the mutant phenotypes of crc and the ecdysone-responsive genes indicate that those genes are likely to h e involved in common signaling pathways.