Animal models of Down syndrome (DS), trisomic for human chromosome 21 (HSA21) genes or orthologs, provide insights into better understanding and treatment options. The only existing transchromosomic (Tc) mouse DS model, Tc1, carries a HSA21 with over 50 protein coding genes (PCGs) disrupted. Tc1 is mosaic, compromising interpretation of results. Here, we “clone” the 34 MB long arm of HSA21 (HSA21q) as a mouse artificial chromosome (MAC). Through multiple steps of microcell-mediated chromosome transfer, we created a new Tc DS mouse model, Tc(HSA21q;MAC)1Yakaz (“TcMAC21”). TcMAC21 is not mosaic and contains 93% of HSA21q PCGs that are expressed and regulatable. TcMAC21 recapitulates many DS phenotypes including anomalies in heart, craniofacial skeleton and brain, molecular/cellular pathologies, and impairments in learning, memory and synaptic plasticity. TcMAC21 is the most complete genetic mouse model of DS extant and has potential for supporting a wide range of basic and preclinical research.
The zebrafish telencephalon is composed of highly specialized subregions that regulate complex behaviors such as learning, memory, and social interactions. The transcriptional signatures of the neuronal types in the telencephalon and the timeline of their emergence from larva to adult remain largely undescribed. Using an integrated analysis of single-cell transcriptomes of approximately 64,000 cells obtained from 6 days post-fertilization (dpf), 15 dpf, and adult telencephalon, we delineated nine main neuronal types in the pallium and eight in the subpallium and nominated novel marker genes. Comparing zebrafish and mouse neuronal types revealed both conserved and absent types and marker genes. Mapping of cell types onto a spatial larval reference atlas created a resource for anatomical and functional studies. Using this multi-age approach, we discovered that while most neuronal subtypes are established early in the 6 dpf fish, some emerge or expand in number later in development. Analyzing the samples from each age separately revealed further complexity in the data, including several cell types that expand substantially in the adult forebrain and do not form clusters at the larval stages. Together, our work provides a comprehensive transcriptional analysis of the cell types in the zebrafish telencephalon and a resource for dissecting its development and function.
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