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APL-1, a Caenorhabditis Elegans Protein Related to the Human ␤-Amyloid Precursor Protein, Is Essential for Viability

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APL-1, a Caenorhabditis Elegans Protein Related to the Human ␤-Amyloid Precursor Protein, Is Essential for Viability APL-1, a Caenorhabditis elegans protein related to the human ␤-amyloid precursor protein, is essential for viability Angela Hornstena, Jason Lieberthalb,c, Shruti Fadiab,d, Richard Malinse,f, Lawrence Hag, Xiaomeng Xug, Isabelle Daigleh, Mindy Markowitzb,i, Gregory O’Connora,j, Ronald Plasterkk, and Chris Lig,h,l Programs in aMolecular Biology, Cell Biology, and Biochemistry and bBiochemistry and Molecular Biology, and Departments of eChemistry and hBiology, Boston University, 5 Cummington Street, Boston, MA 02215; gDepartment of Biology, City College of the City University of New York, 160 Convent Avenue, New York, NY 10031; and kHubrecht Laboratory, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands Edited by Iva S. Greenwald, Columbia University, New York, NY, and approved December 8, 2006 (received for review May 15, 2006) Dominant mutations in the amyloid precursor protein (APP) gene are APP transgene (15). Expression of human APP in Drosophila associated with rare cases of familial Alzheimer’s disease; however, wing imaginal discs results in a blistered wing phenotype, the normal functions of APP and related proteins remain unclear. The showing that overexpression of APP can disrupt cell adhesion in nematode Caenorhabditis elegans has a single APP-related gene, the transgenic animals (16). apl-1, that is expressed in multiple tissues. Loss of apl-1 disrupts In this article, we examine the role of apl-1 in C. elegans. several developmental processes, including molting and morphogen- Zambrano et al. (17) have reported mild pharyngeal defects when esis, and results in larval lethality. The apl-1 lethality can be rescued apl-1 activity is decreased by dsRNA-mediated interference by by neuronal expression of the extracellular domain of APL-1. These feeding. We genetically inactivated apl-1 and found that, like the data highlight the importance of the extracellular domain of an APP mammalian APP gene family, apl-1 has an essential role in C. family member and suggest that APL-1 acts noncell-autonomously elegans. In particular, APL-1 is necessary for proper molting and during development. Overexpression of APL-1 also causes several morphogenesis. Furthermore, expression of the extracellular do- defects, including a high level of larval lethality. Decreased activity of main of APL-1 in neurons is sufficient to rescue the apl-1 lethality. sel-12,aC. elegans homologue of the human ␥-secretase component These data highlight the significance of the extracellular domain of presenilin 1, partially rescues the lethality associated with APL-1 APL-1 and perhaps other APP-related proteins. overexpression, suggesting that SEL-12 activity regulates APL-1 ac- tivity either directly or indirectly. Results and Discussion apl-1 Is Expressed in Multiple Cell Types. apl-1 (C42D8.8) maps to Alzheimer’s disease ͉ genetics ͉ model system the X chromosome and contains 12 exons (Fig. 1A). Like mammalian APP (3), APL-1 undergoes glycosylation and cleav- age to release a large extracellular domain (sAPL-1; Fig. 1D). To lzheimer’s Disease (AD) is a progressive neurodegenerative determine the expression pattern of apl-1, we generated animals Adisorder that is characterized pathologically by the accu- carrying transcriptional and translational GFP reporter trans- mulation of dense plaques in the brains of AD patients. The main ␤ genes. All transgenic lines exhibited comparable expression component of these plaques is the -amyloid peptide (1, 2), patterns. Similar to the widespread expression of mammalian which is a cleavage product of the amyloid precursor protein APP (for review see ref. 18), apl-1 expression was detected in (APP; ref. 3). Autosomal dominant mutations in APP have been Ͼ50 neuronal, muscle, hypodermal, and supporting cells in correlated with a small number of early-onset AD cases (see adults [Fig. 2 and supporting information (SI) Fig. 4]. The larval Alzheimer’s Disease Mutation Database at www.molgen.ua. expression pattern was similar to the adult pattern with a few ac.be/ADMutations). Although APP has been implicated in exceptions; for instance, apl-1 is expressed in more ventral cord NEUROSCIENCE several processes in vitro, such as neurite outgrowth, cell adhe- motor neurons in the first larval stage (L1) animals than in other sion, and cell survival (for review see ref. 4), the in vivo functions larval stages or adults (data not shown). of APP remain unclear. Determining the in vivo functions of APP in mammals is com- apl-1 Is Essential for Viability. To determine the function of apl-1, plicated by the presence of two APP-related genes, APLP1 and we isolated a strain (pk53 apl-1:Tc1) containing a Tc1 transposon 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 Author contributions: A.H. and C.L. designed research; A.H., J.L., S.F., R.M., L.H., X.X., G.O., contain the ␤-amyloid peptide (5). Mice in which APP, APLP1,or and C.L. performed research; I.D., M.M. and R.P. contributed new reagents/analytic tools; APLP2 is inactivated are viable and have minor behavioral and A.H., J.L., S.F., R.M., L.H., X.X., I.D., and C.L. analyzed data; and C.L. wrote the paper. growth deficits (6–8). However, inactivation of APLP2 and either The authors declare no conflict of interest. APP or APLP1 results in early postnatal lethality (6, 8), indicating This article is a PNAS direct submission. that the APP family is essential for viability. The brains of double Abbreviation: APP, amyloid precursor protein. knockout animals exhibit no obvious morphological defects (6, 8). cPresent address: Department of Microbiology, New York University School of Medicine, By contrast, animals in which the entire APP gene family is New York, NY 10016. inactivated show cortical dysplasia and type 2 lissencephaly, indi- dPresent address: Robert Wood Johnson Medical School, Piscataway, NJ 08854. cating that the APP gene family is necessary for neurodevelopment fPresent address: Department of Pharmacology, Oxford University, Oxford OX1 3QT, and adhesion (9). United Kingdom. Although no APP gene has been identified in Drosophila iPresent address: Department of Medicine, Lenox Hill Hospital, New York, NY 10021. melanogaster or Caenorhabditis elegans, each organism contains jPresent address: Novartis Institutes for Biomedical Research, Cambridge, MA 02139. a single APP-related gene (10, 11). Inactivation of the Drosophila lTo whom correspondence should be addressed. E-mail: [email protected]. APP-related gene, Appl, causes abnormal synaptic differentia- This article contains supporting information online at www.pnas.org/cgi/content/full/ tion (12), axonal transport (13, 14), and phototactic behavior 0603997104/DC1. (15), the latter of which can be partially rescued with a human © 2007 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0603997104 PNAS ͉ February 6, 2007 ͉ vol. 104 ͉ no. 6 ͉ 1971–1976 Downloaded by guest on September 27, 2021 Fig. 2. APL-1 is expressed in multiple cell types. (A) Head region of an adult animal carrying a GFP transcriptional reporter construct under the control of an apl-1 promoter shown in a lateral view. apl-1 is expressed in a variety of cell types, including neurons (indicated by their three letter names; where the identity of the neurons is between two cells, both possibilities are indicated), muscle cells, and supporting cells. Many processes in the nerve ring, the major neuropil region of the animal, and various nerve bundles (arrows) also express apl-1. Gut granules within intestinal cells (arrowheads) often show nonspecific fluorescence. MNs, motor neurons. (B)InynIs79 APL-1::GFP animals, GFP expression is faint and punctate, suggesting that APL-1::GFP is located in vesicular compartments of the cell. The cells that exhibit apl-1 expression, however, are the same as those in A. (Scale bars: A,25␮m; B,10␮m.) Fig. 1. Molecular characterization of apl-1 alleles. (A) Schematic of the apl-1 genomic locus. The gray boxes represent the regions encoding the extracel- insertion in the apl-1 gene (Fig. 1A) and screened for imprecise lular domain of APL-1, the striped box indicates the transmembrane (TMD) transposon excisions that deleted parts of the apl-1 coding Ј and cytoplasmic domains, and the open box indicates the 3 UTR. apl-1 is region. We isolated two deletion mutants: yn5 (see below) and trans-spliced, so the start site of transcription is unknown. Locations of the Tc1 insertion (inverted triangle), apl-1 point mutations, and yn5 and yn10 dele- yn10 (Fig. 1A and SI Text). Because yn10 mutants produced no tions are indicated (see SI Text for exact lesions). AMB, OCH, and OPA indicate detectable APL-1 protein (Fig. 1C), we concluded that yn10 is a amber, ochre, and opal stop codons, respectively. (B) Schematic of proteins null allele. To isolate additional apl-1 alleles, we performed F1 encoded by constructs tested for rescue of the apl-1 lethality. The signal noncomplementation screens and isolated five more alleles: sequence (circles), extracellular E1 (amino acids 1–209) and E2 (amino acids yn23, yn29, yn30, yn31, and yn32. All of the isolated alleles ␣ 236–423) domains, TMD (gray box), cytoplasmic domain (C), and putative Go correspond to point mutations within the coding region of the binding site (striped boxes) are shown. Chimeric proteins with GFP are indi- cated; APL-1::GFP lines carry an apl-1 genomic fragment or cDNA fused to GFP. extracellular domain and cause phenotypes similar to yn10 (Fig. The number of lines that rescued the given apl-1 mutation relative to the total 1A and SI Text). number of independent transgenic lines is shown. ND, not determined. (C) apl-1(yn10) and the isolated point mutations cause a recessive yn10, yn23, and yn32 are likely null alleles.
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