Amyloid precursor protein regulates neurogenesis by antagonizing miR-574-5p in the developing cerebral cortex

Amyloid precursor protein (APP) is a transmembrane glycoprotein proteolytically processed to release amyloid beta, a pathological hallmark of Alzheimer's disease. APP is expressed throughout the developing and mature brain; however, the primary function of this protein is unknown. We previously demonstrated that APP deficiency enhances neurogenesis, but the mechanisms underlying this process are not known. Here we show that APP regulates the expression of microRNAs in the cortex and in neural progenitors, specifically repressing miR-574-5p. We also show that overexpression of miR-574-5p promotes neurogenesis, but reduces the neural progenitor pool. In contrast, the reduced expression of miR-574-5p inhibits neurogenesis and stimulates proliferation in vitro and in utero. We further demonstrate that the inhibition of miR-574-5p in APP-knockout mice rescues the phenotypes associated with APP deficiency in neurogenesis. Taken together, these results reveal a mechanism in which APP regulates the neurogenesis through miRNA-mediated post-transcriptional regulation.

[1]  R. Nitsch,et al.  Nuclear signaling by the APP intracellular domain occurs predominantly through the amyloidogenic processing pathway , 2009, Journal of Cell Science.

[2]  M. Locker,et al.  Noxp20 and Noxp70, two new markers of early neuronal differentiation, detected in teratocarcinoma‐derived neuroectodermic precursor cells , 2006, Journal of neurochemistry.

[3]  Yutaka Kirino,et al.  Cleavage of Alzheimer’s Amyloid Precursor Protein (APP) by Secretases Occurs after O-Glycosylation of APP in the Protein Secretory Pathway , 1998, The Journal of Biological Chemistry.

[4]  D. Bartel.  MicroRNAs: Target Recognition and Regulatory Functions , 2009, Cell.

[5]  T. Dalmay,et al.  Identification of new central nervous system specific mouse microRNAs , 2006, FEBS letters.

[6]  G. Kusek,et al.  Asymmetric segregation of the double-stranded RNA binding protein Staufen2 during mammalian neural stem cell divisions promotes lineage progression. , 2012, Cell stem cell.

[7]  Perspective , 1974 .

[8]  M. Quiñones,et al.  Patterns of microRNA Expression in Non-Human Primate Cells Correlate with Neoplastic Development In Vitro , 2010, PloS one.

[9]  N. Rajewsky,et al.  The evolution of gene regulation by transcription factors and microRNAs , 2007, Nature Reviews Genetics.

[10]  V. Ambros,et al.  Expression profiling of mammalian microRNAs uncovers a subset of brain-expressed microRNAs with possible roles in murine and human neuronal differentiation , 2004, Genome Biology.

[11]  Martin Kuiper,et al.  BiNGO: a Cytoscape plugin to assess overrepresentation of Gene Ontology categories in Biological Networks , 2005, Bioinform..

[12]  M. Wegner,et al.  Sox12 Deletion in the Mouse Reveals Nonreciprocal Redundancy with the Related Sox4 and Sox11 Transcription Factors , 2008, Molecular and Cellular Biology.

[13]  Thomas Rülicke,et al.  Behavioral and anatomical deficits in mice homozygous for a modified β-amyloid precursor protein gene , 1994, Cell.

[14]  Véronique Lefebvre,et al.  The three SoxC proteins—Sox4, Sox11 and Sox12—exhibit overlapping expression patterns and molecular properties , 2008, Nucleic acids research.

[15]  C. Burge,et al.  Conserved Seed Pairing, Often Flanked by Adenosines, Indicates that Thousands of Human Genes are MicroRNA Targets , 2005, Cell.

[16]  Terence P. Speed,et al.  A comparison of normalization methods for high density oligonucleotide array data based on variance and bias , 2003, Bioinform..

[17]  Toshiharu Suzuki,et al.  Role of APP phosphorylation in FE65‐dependent gene transactivation mediated by AICD , 2006, Genes to cells : devoted to molecular & cellular mechanisms.

[18]  A. Hatzigeorgiou,et al.  A guide through present computational approaches for the identification of mammalian microRNA targets , 2006, Nature Methods.

[19]  Qihong Huang,et al.  MicroRNAs can regulate human APP levels , 2008, Molecular Neurodegeneration.

[20]  Henry Yang,et al.  MicroRNA-125b Promotes Neuronal Differentiation in Human Cells by Repressing Multiple Targets , 2009, Molecular and Cellular Biology.

[21]  Ana Kozomara,et al.  miRBase: integrating microRNA annotation and deep-sequencing data , 2010, Nucleic Acids Res..

[22]  Li-Huei Tsai,et al.  Trekking across the Brain: The Journey of Neuronal Migration , 2007, Cell.

[23]  Olga Varlamova,et al.  A cAMP-response element binding protein-induced microRNA regulates neuronal morphogenesis. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[24]  M. Covic,et al.  Expression of Sox11 in adult neurogenic niches suggests a stage‐specific role in adult neurogenesis , 2009, The European journal of neuroscience.

[25]  L. Van Aelst,et al.  DOCK7 interacts with TACC3 to regulate interkinetic nuclear migration and cortical neurogenesis , 2012, Nature Neuroscience.

[26]  Véronique Lefebvre,et al.  Organogenesis relies on SoxC transcription factors for the survival of neural and mesenchymal progenitors , 2010, Nature communications.

[27]  R. Boonstra,et al.  The utility of Ki-67 and BrdU as proliferative markers of adult neurogenesis , 2002, Journal of Neuroscience Methods.

[28]  Xiaozhong Peng,et al.  MicroRNA-16 targets amyloid precursor protein to potentially modulate Alzheimer's-associated pathogenesis in SAMP8 mice , 2012, Neurobiology of Aging.

[29]  S. Taviaux,et al.  SOX22 is a new member of the SOX gene family, mainly expressed in human nervous tissue. , 1997, Human molecular genetics.

[30]  M. Schachner,et al.  A TAG1-APP signalling pathway through Fe65 negatively modulates neurogenesis , 2008, Nature Cell Biology.

[31]  H. Tabata,et al.  Neurons tend to stop migration and differentiate along the cortical internal plexiform zones in the Reelin signal‐deficient mice , 2002, Journal of neuroscience research.

[32]  Y. Suh,et al.  Phosphorylation of Amyloid Precursor Protein (APP) at Thr668 Regulates the Nuclear Translocation of the APP Intracellular Domain and Induces Neurodegeneration , 2006, Molecular and Cellular Biology.

[33]  Kenneth S. Kosik,et al.  The Elegance of the MicroRNAs: A Neuronal Perspective , 2005, Neuron.

[34]  Stijn van Dongen,et al.  miRBase: microRNA sequences, targets and gene nomenclature , 2005, Nucleic Acids Res..

[35]  G. Tsongalis,et al.  MicroRNAs: novel biomarkers for human cancer. , 2009, Clinical chemistry.

[36]  P. Greengard,et al.  Role of Phosphorylation of Alzheimer’s Amyloid Precursor Protein during Neuronal Differentiation , 1999, The Journal of Neuroscience.

[37]  G. Milligan,et al.  Role of MicroRNAs 99b, 181a, and 181b in the Differentiation of Human Embryonic Stem Cells to Vascular Endothelial Cells , 2012, Stem cells.

[38]  A. Delacourte,et al.  MicroRNA regulation of Alzheimer's Amyloid precursor protein expression , 2009, Neurobiology of Disease.