Down syndrome (DS), or trisomy 21 (Ts21), is the most common genetic developmental disorder with a prevalence of about one in 700 live births. The triplication of human chromosome 21 (Hsa21) that characterizes this disorder results in a constellation of cognitive and physical alterations. The cognitive deficits range from mild to severe, and persist throughout life. Post-mortem studies of individuals with DS have revealed various neuropathologic abnormalities that are thought to underlie cognitive dysfunction, including: disruption of neurogenesis, corticogenesis, synapse formation, and myelination. However, the etiology of these alterations remains largely unknown. In order to elucidate the genetic basis of DS-phenotypes, several mouse models have been developed. The Ts65Dn, Ts1Cje, and Ts16 models, recapitulate DS-related phenotypes and have extended our knowledge of the associated pathological changes. Despite this progress, genetic dissimilarities in mouse models may confound phenotypic comparisons between mouse models and human DS. Specifically, the aforementioned models have a limited subset of triplicated Hsa-21 homologs or contain non-syntenic genes. Recently, a novel mouse model, the Dp(16)1Yey/+ (or Dp16), that has the entire Hsa-21 syntenic region of Mmu16 triplicated and no non-syntenic genes has been developed, suggesting that Dp16 may present phenotypes more closely matching the human disorder. In this study, we present the first comprehensive analysis of Dp16 embryonic, young and adult brains that includes a focus on the proliferative, inhibitory/excitatory neuronal and oligodendrocyte-lineage phenotypes using histological, immunohistochemical, and behavioral assessments. We hypothesize that due to the larger triplicated segment, the Dp16 mouse model better recapitulates DS-related neuropathologies relative to other mouse models. Despite the extended triplication, Dp16 animals lack DS-related embryonic phenotypes, however, behavioral and cellular phenotypes arise during the 2nd week following birth. The Dp16 is the first model of DS to develop postnatal phenotypes in the absence of changes to embryonic brain development, as such, Dp16 may not be a reliable model to further understand brain development in the DS fetus. However, when used in conjuncture with other models, the Dp16 will be a useful tool in understanding the contribution of aneuploidy and gene dosage to DS-phenotypes in mouse models of DS.
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/16723 |
| Date | 15 June 2016 |
| Creators | Goodliffe, Joseph White |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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