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Generation of improved human cerebral organoids from single copy DYRK1A knockout induced pluripotent stem cells in trisomy 21: hypothetical solutions for neurodevelopmental models and therapeutic alternatives in down syndrome
Author(s) -
Çağlayan E. Sacide
Publication year - 2016
Publication title -
cell biology international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.932
H-Index - 77
eISSN - 1095-8355
pISSN - 1065-6995
DOI - 10.1002/cbin.10694
Subject(s) - dyrk1a , corticogenesis , microcephaly , down syndrome , induced pluripotent stem cell , phenotype , palbociclib , organoid , biology , phosphoproteomics , chromosome 21 , hippocampal formation , neuroscience , kinase , embryonic stem cell , stem cell , microbiology and biotechnology , progenitor cell , genetics , protein kinase a , cancer , gene , chromosome , metastatic breast cancer , breast cancer , protein phosphorylation
Dual‐specificity thyrosine phosphorylation‐regulated kinase 1A (DYRK1A) is a strong therapeutic target to ameliorate cognitive functions of Down Syndrome (DS). Genetic normalization of Dyrk1a is sufficient to normalize early cortical developmental phenotypes in DS mouse models. Gyrencephalic human neocortical development is more complex than that in lissencephalic mice; hence, cerebral organoids (COs) can be used to model early neurodevelopmental defects of DS. Single copy DYRK1A knockout COs (sc DYRK1A KO‐COs) can be generated from manipulated DS derived (DS‐) induced pluripotent stem cells (iPSCs) and genetic normalization of DYRK1A is expected to result in corrected neurodevelopmental phenotypes that can be reminiscent of normal COs. DYRK1A knock‐in ( DYRK1A KI) COs can be derived after genetic manipulations of normal iPSCs and would be valuable to evaluate impaired neocortical development as can be seen in DS‐COs. DYRK1A mutations cause severe human primary microcephaly; hence, dose optimization studies of DYRK1A inhibitors will be critical for prenatal therapeutic applications in DS. Several doses of DYRK1A inhibitors can be tested in the neurodevelopment process of DS‐COs and DS‐sc DYRK1A KO‐COs would be used as optimum models for evaluating phenotypic ameliorations. Overdose drug exposure in DS‐COs can be explained by similar defects present in DS‐ba DYRK1A KO‐COs and DYRK1A KO‐COs. There are several limitations in the current CO technology, which can be reduced by the generation of vascularized brain‐like organoids giving opportunities to mimic late‐stage corticogenesis and complete hippocampal development. In the future, improved DS‐ DYRK1A KO‐COs can be efficient in studies that aim to generate efficiently transplantable and implantable neurons for tissue regeneration alternatives in DS individuals.