Dominant mutations in the amyloid precursor protein (APP) gene are associated with rare cases of familial Alzheimer's disease; however, the normal functions of APP and related proteins remain unclear. The nematode Caenorhabditis elegans has a single APP-related gene, apl-1, that is expressed in multiple tissues. Loss of apl-1 disrupts several developmental processes, including molting and morphogenesis, and results in larval lethality. The apl-1 lethality can be rescued by neuronal expression of the extracellular domain of APL-1. These data highlight the importance of the extracellular domain of an APP family member and suggest that APL-1 acts noncell-autonomously during development. Overexpression of APL-1 also causes several defects, including a high level of larval lethality. Decreased activity of sel-12, a C. elegans homologue of the human ␥-secretase component presenilin 1, partially rescues the lethality associated with APL-1 overexpression, suggesting that SEL-12 activity regulates APL-1 activity either directly or indirectly. Determining the in vivo functions of APP in mammals is complicated by the presence of two APP-related genes, APLP1 and APLP2 (for review see ref. 5). APP and APP-related proteins share two conserved domains in the extracellular region (E1 and E2) and one in the cytoplasmic domain, but the APP-related proteins do not contain the ␤-amyloid peptide (5). Mice in which APP, APLP1, or APLP2 is inactivated are viable and have minor behavioral and growth deficits (6-8). However, inactivation of APLP2 and either APP or APLP1 results in early postnatal lethality (6,8), indicating that the APP family is essential for viability. The brains of double knockout animals exhibit no obvious morphological defects (6, 8). By contrast, animals in which the entire APP gene family is inactivated show cortical dysplasia and type 2 lissencephaly, indicating that the APP gene family is necessary for neurodevelopment and adhesion (9).Although no APP gene has been identified in Drosophila melanogaster or Caenorhabditis elegans, each organism contains a single APP-related gene (10, 11). Inactivation of the Drosophila APP-related gene, Appl, causes abnormal synaptic differentiation (12), axonal transport (13,14), and phototactic behavior (15), the latter of which can be partially rescued with a human APP transgene (15). Expression of human APP in Drosophila wing imaginal discs results in a blistered wing phenotype, showing that overexpression of APP can disrupt cell adhesion in the transgenic animals (16).In this article, we examine the role of apl-1 in C. elegans. Zambrano et al. (17) have reported mild pharyngeal defects when apl-1 activity is decreased by dsRNA-mediated interference by feeding. We genetically inactivated apl-1 and found that, like the mammalian APP gene family, apl-1 has an essential role in C. elegans. In particular, APL-1 is necessary for proper molting and morphogenesis. Furthermore, expression of the extracellular domain of APL-1 in neurons is sufficient to rescue the apl-1 lethality. Th...