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Implications for Chromosome 21-Encoded miRNAs and MeCP2 in Synaptic Dysfunction in Trisomy 21

by
Heather McGowan
B.A., The College of New Jersey - 2008

Thesis Advisor: Zhiping Pang, M.D., Ph.D.
Graduate Program in Neuroscience

CHINJ, Room 3101
New Brunswick

Monday, April 24, 2017
3:00 p.m.


Abstract

The formation and maintenance of synaptic connections is highly regulated. Emerging evidence implicates non-coding RNAs, including microRNAs (miRNAs), in regulating synaptic development and function, and therefore, over- or under-expression of miRNAs may contribute to synaptic dysfunction in neurodevelopmental disorders. Trisomy 21 (T21) is characterized by a number of clinical hallmarks, including cognitive impairment and mild to moderate intellectual disability. Animal models and human induced pluripotent stem (iPS) cell models have demonstrated synaptic aberrations, including altered synaptic density and reduced synaptic connectivity. Utilizing the innovative induced neuronal (iN) cell technology, we have investigated the role of miRNAs encoded by human chromosome 21 (HSA21) in synaptic development and function in human iN cells, with a special emphasis on hsa-let-7c. We have verified that T21 results in the increased expression of several miRNAs, including hsa-let-7c, which target the methyl CpG binding protein 2 (MeCP2), which is mutated in Rett syndrome and vital for neuronal and synaptic development and function.
We have studied the effects of let-7 miRNAs on synaptogenesis in human neurons by overexpressing hsa-let-7c in control (i.e. euploid) iN cells, and in turn by antagonizing its expression in T21 iN cells. Overexpression of hsa-let-7c in control iNs decreases the expression of MeCP2 and results in reductions in soma size, dendritic complexity, synapse density, and synaptic transmission. RNA sequencing confirms that gene networks involved in synaptic transmission, as well as neurite extension are perturbed by hsa-let-7c overexpression. Moreover, antagonizing the overexpression of hsa-let-7c in T21 iN cells restores MeCP2 levels and rescues the density of synaptic connections. By combining interdisciplinary analytical methodologies with the iN cell and iPS cell technologies to examine the functions of hsa-let-7c in the nervous system, we have broadened our overall knowledge of its role in regulating synaptic development and provided important insight into its potential contribution to the synaptic pathophysiology seen in T21 neurons.


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