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      Lithium as a possible therapeutic strategy for Cornelia de Lange syndrome

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          Abstract

          Cornelia de Lange Syndrome (CdLS) is a rare developmental disorder affecting a multitude of organs including the central nervous system, inducing a variable neurodevelopmental delay. CdLS malformations derive from the deregulation of developmental pathways, inclusive of the canonical WNT pathway. We have evaluated MRI anomalies and behavioral and neurological clinical manifestations in CdLS patients. Importantly, we observed in our cohort a significant association between behavioral disturbance and structural abnormalities in brain structures of hindbrain embryonic origin. Considering the cumulative evidence on the cohesin-WNT-hindbrain shaping cascade, we have explored possible ameliorative effects of chemical activation of the canonical WNT pathway with lithium chloride in different models: (I) Drosophila melanogaster CdLS model showing a significant rescue of mushroom bodies morphology in the adult flies; (II) mouse neural stem cells restoring physiological levels in proliferation rate and differentiation capabilities toward the neuronal lineage; (III) lymphoblastoid cell lines from CdLS patients and healthy donors restoring cellular proliferation rate and inducing the expression of CyclinD1. This work supports a role for WNT-pathway regulation of CdLS brain and behavioral abnormalities and a consistent phenotype rescue by lithium in experimental models.

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          Mediator and Cohesin Connect Gene Expression and Chromatin Architecture

          Summary Transcription factors control cell specific gene expression programs through interactions with diverse coactivators and the transcription apparatus. Gene activation may involve DNA loop formation between enhancer-bound transcription factors and the transcription apparatus at the core promoter, but this process is not well understood. We report here that Mediator and Cohesin physically and functionally connect the enhancers and core promoters of active genes in embryonic stem cells. Mediator, a transcriptional coactivator, forms a complex with Cohesin, which can form rings that connect two DNA segments. The Cohesin loading factor Nipbl is associated with Mediator/Cohesin complexes, providing a means to load Cohesin at promoters. DNA looping is observed between the enhancers and promoters occupied by Mediator and Cohesin. Mediator and Cohesin occupy different promoters in different cells, thus generating cell-type specific DNA loops linked to the gene expression program of each cell.
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            Wnt/Ca2+ signaling pathway: a brief overview.

            Antara De (2011)
            The non-canonical Wnt/Ca(2+) signaling cascade is less characterized than their canonical counterpart, the Wnt/β-catenin pathway. The non-canonical Wnt signaling pathways are diverse, defined as planer cell polarity pathway, Wnt-RAP1 signaling pathway, Wnt-Ror2 signaling pathway, Wnt-PKA pathway, Wnt-GSK3MT pathway, Wnt-aPKC pathway, Wnt-RYK pathway, Wnt-mTOR pathway, and Wnt/calcium signaling pathway. All these pathways exhibit a considerable degree of overlap between them. The Wnt/Ca(2+) signaling pathway was deciphered as a crucial mediator in development. However, now there is substantial evidence that the signaling cascade is involved in many other molecular phenomena. Many aspects of Wnt/Ca(2+) pathway are yet enigmatic. This review will give a brief overview of the fundamental and evolving concepts of the Wnt/Ca(2+) signaling pathway.
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              Can we safely target the WNT pathway?

              WNT-β-catenin signalling is involved in a multitude of developmental processes and the maintenance of adult tissue homeostasis by regulating cell proliferation, differentiation, migration, genetic stability and apoptosis, as well as by maintaining adult stem cells in a pluripotent state. Not surprisingly, aberrant regulation of this pathway is therefore associated with a variety of diseases, including cancer, fibrosis and neurodegeneration. Despite this knowledge, therapeutic agents specifically targeting the WNT pathway have only recently entered clinical trials and none has yet been approved. This Review examines the problems and potential solutions to this vexing situation and attempts to bring them into perspective.
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                Author and article information

                Contributors
                valentina.massa@unimi.it
                Journal
                Cell Death Discov
                Cell Death Discov
                Cell Death Discovery
                Nature Publishing Group UK (London )
                2058-7716
                17 February 2021
                17 February 2021
                2021
                : 7
                : 34
                Affiliations
                [1 ]GRID grid.4708.b, ISNI 0000 0004 1757 2822, Department of Health Sciences, , Università degli Studi di Milano, ; Milan, Italy
                [2 ]UOC Pediatria, ASST Lariana, Como, Italy
                [3 ]GRID grid.4708.b, ISNI 0000 0004 1757 2822, “Aldo Ravelli” Center for Neurotechnology and Experimental Brain Therapeutics, , Università degli Studi di Milano, ; Milan, Italy
                [4 ]Department of Pediatrics-ASST Papa Giovanni XXIII, Bergamo, Italy
                [5 ]GRID grid.5608.b, ISNI 0000 0004 1757 3470, Department of Pediatrics, , University of Padova, ; Padova, Italy
                [6 ]GRID grid.11451.30, ISNI 0000 0001 0531 3426, Department of Pediatrics and Internal Medicine Nursing, Department of Rare Disorders, , Medical University of Gdansk, ; Gdańsk, Poland
                [7 ]GRID grid.414818.0, ISNI 0000 0004 1757 8749, Child and Adolescent Neuropsychiatric Unit, , Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, ; Milan, Italy
                [8 ]GRID grid.4708.b, ISNI 0000 0004 1757 2822, Department of Biosciences, , Università degli Studi di Milano, ; Milano, Italy
                Author information
                http://orcid.org/0000-0001-9120-4217
                http://orcid.org/0000-0002-2689-2049
                http://orcid.org/0000-0002-7951-9512
                http://orcid.org/0000-0002-7808-7578
                Article
                414
                10.1038/s41420-021-00414-2
                7889653
                33597506
                32d85de6-8464-47ee-a1a0-18d47f9d356e
                © The Author(s) 2021

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 1 December 2020
                : 28 December 2020
                : 17 January 2021
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100002803, Fondazione Cariplo (Cariplo Foundation);
                Award ID: 2015-0783
                Award Recipient :
                Funded by: Università degli Studi di Milano Intramural Fundings; Nickel and Co S.p.A.; CRC Aldo Ravelli
                Funded by: Molecular and Translational Medicine PhD-Università degli Studi di Milano scholarship
                Funded by: FundRef https://doi.org/10.13039/501100005010, Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research);
                Award ID: 20661
                Award ID: 20661
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100011713, Worldwide Cancer Research;
                Award ID: 18-0399
                Award ID: 18-0399
                Award Recipient :
                Categories
                Article
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                © The Author(s) 2021

                differentiation,disease model,neurodevelopmental disorders

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