Alzheimer's disease is a neurodegenerative disorder that causes a progressive decline of mental and cognitive processes such as memory, judgment and reasoning. We proposed earlier that a sustained loss of function of Wnt/β- catenin signaling components underlies the onset and progression of the disease. Here, we discuss recent data on the involvement of Wnt/b-catenin signaling on amyloid precursor protein (APP) processing, Aβ peptide neurotoxicity, τ phosphorylation, and modulation of Apolipoprotein E function in the brain. We conclude that several components of the cascade are actively engaged in the events leading to AD neuropathology and propose that compounds that mimic activation of this signaling cascade, such as lithium, should be considered for therapeutic intervention in Alzheimer's patients. In summary, data accumulated during the past decade confirm some important predictions of our hypothesis where components of this signaling cascade are actively engaged in the events leading to AD neuropathology and that compounds that mimic activation of this signaling cascade, such as lithium, should be considered for therapeutic intervention in Alzheimer's patients.

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Key Points• Wnt/b-catenin signaling increases ETO and Runx1 transcription in human hematopoietic progenitors.• Wnt/b-catenin signaling enhances spatial proximity of ETO and RUNX1 genes and induces the generation of a recurrent translocation event.Chromosomal translocations are frequently associated with a wide variety of cancers, particularly hematologic malignancies. A recurrent chromosomal abnormality in acute myeloid leukemia is the reciprocal translocation t(8;21) that fuses RUNX1 and ETO genes. We report here that Wnt/b-catenin signaling increases the expression of ETO and RUNX1 genes in human hematopoietic progenitors. We found that b-catenin is rapidly recruited into RNA polymerase II transcription factories (RNAPII-Ser5) and that ETO and RUNX1 genes are brought into close spatial proximity upon Wnt3a induction. Notably, long-term treatment of cells with Wnt3a induces the generation a frequent RUNX1-ETO translocation event. Thus, Wnt/b-catenin signaling induces transcription and translocation of RUNX1 and ETO fusion gene partners, opening a novel window to understand the onset/ development of leukemia. (Blood. 2015;126(15):1785-1789) IntroductionOne of the most common chromosomal abnormalities in acute myeloid leukemia (AML) is the reciprocal translocation t(8;21)(q22;q22), which involves the RUNX1 (AML1) and the ETO (RUNX1T1) genes and produces a Runx1-ETO fusion transcript that inhibits Runx1-dependent transcriptional regulation. 1,2 Although RUNX1-ETO translocations could act as initiating events in hematopoietic stem cells (HSCs), after which leukemia clonally evolves through the acquisition of secondary mutations, 3,4 the molecular mechanism and cellular signals that drive the generation of the t(8;21) translocation remain to be elucidated.Although much has been learned in recent years about the onset or development of AML from studies examining Runx1 expression or function, [5][6][7][8] we are still far from a complete understanding of the cellular mechanisms controlling the transcription of its translocation partner, ETO.9-11 Considering that Wnt/b-catenin plays essential roles during the proliferation or differentiation of HSCs and that reactivation of b-catenin signaling is important for selfrenewal of leukemia stem cells, 12-14 we studied whether Wnt/ b-catenin signaling was involved in ETO expression and RUNX1-ETO fusion. Methods Human CD341 cells and cell lines Results and discussionAccording to the current assembly of the human genome (GRCh38), the ETO gene consists of 17 exons distributed over 148 kb ( Figure 1A The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 USC section 1734. For personal use only. on May 11, 2018. by guest www.bloodjournal.org From and its expression generates multiple messenger RNA (mRNA) isoforms by alternative splicing or the use of different promoters. [9][10][11] We searched for core TCF/LEF-binding elements (TBE: CTTTG)...

Synaptic abnormalities have been described in individuals with autism spectrum disorders (ASD). The cell-adhesion molecule Neuroligin-3 (Nlgn3) has an essential role in the function and maturation of synapses and NLGN3 ASD-associated mutations disrupt hippocampal and cortical function. Here we show that Wnt/β-catenin signaling increases Nlgn3 mRNA and protein levels in HT22 mouse hippocampal cells and primary cultures of rat hippocampal neurons. We characterized the activity of mouse and rat Nlgn3 promoter constructs containing conserved putative T-cell factor/lymphoid enhancing factor (TCF/LEF)-binding elements (TBE) and found that their activity is significantly augmented in Wnt/β-catenin cell reporter assays. Chromatin immunoprecipitation (ChIP) assays and site-directed mutagenesis experiments revealed that endogenous β-catenin binds to novel TBE consensus sequences in the Nlgn3 promoter. Moreover, activation of the signaling cascade increased Nlgn3 clustering and co- localization with the scaffold PSD-95 protein in dendritic processes of primary neurons. Our results directly link Wnt/β-catenin signaling to the transcription of the Nlgn3 gene and support a functional role for the signaling pathway in the dysregulation of excitatory/inhibitory neuronal activity, as is observed in animal models of ASD.

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