The expression of the Alzheimer's amyloid precursor protein-like gene is regulated by developmental timing microRNAs and their targets in Caenorhabditis elegans.
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of dense plaques in the brain, resulting in progressive dementia. A major plaque component is the beta-amyloid peptide, which is a cleavage product of the amyloid precursor protein (APP). Studies of dominant inheritable familial AD support the hypothesis that APP is critical for AD development. On the other hand, the pathogenesis of amyloid plaque deposition in AD is thought to be the result of age-related changes with unknown mechanisms. Here we show that the Caenorhabditis elegans homolog of APP, APP-like-1 (apl-1), functions with and is under the control of molecules regulating developmental progression. In C. elegans, the timing of cell fate determination is controlled by the heterochronic genes, including let-7 microRNAs. C. elegans apl-1 shows significant genetic interactions with let-7 family microRNAs and let-7-targeted heterochronic genes, hbl-1, lin-41 and lin-42. apl-1 expression is upregulated during the last larval stage in hypodermal seam cells which is transcriptionally regulated by hbl-1, lin-41 and lin-42. Moreover, the levels of the apl-1 transcription are modulated by the activity of let-7 family microRNAs. Our work places apl-1 in a developmental timing pathway and may provide new insights into the time-dependent progression of AD.
Niwa
Ryusuke
R
Department of Molecular, Cellular and Developmental Biology, KBT 936, Yale University, PO Box 208103, 266 Whitney Avenue, New Haven, CT 06520, USA.
Zhou
Feng
F
Li
Chris
C
Slack
Frank J
FJ
D000544:Alzheimer Disease / Q000209:etiology; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000254:growth & development* / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D017238:Genes, Helminth; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D034622:RNA Interference; D018510:RNA, Helminth / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics
D029742:Caenorhabditis elegans Proteins; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D035683:MicroRNAs; D018510:RNA, Helminth; D014157:Transcription Factors; C084891:APL-1 protein, C elegans; C410586:LIN-41 protein, C elegans; C400538:LIN-42 protein, C elegans; C474486:hbl-1 protein, C elegans; C474488:let-7 microRNA, C elegans