Date of Award

2018

Document Type

Honors Thesis (Colby Access Only)

Department

Colby College. Biology Dept.

Advisor(s)

Tariq Ahmad

Second Advisor

Joshua Kavaler

Third Advisor

David Angelini, Ed Yeterian

Abstract

A variant of the human CHMP2B gene (CHMP2BIntron5), which is associated with frontotemporal dementia linked to chromosome 3 (FTD3), has previously been shown to disrupt cell signaling pathways and cause developmental and neurodegenerative effects when expressed in the Drosophila eye. To further examine the role of CHMP2BIntron5 in a neural developmental model system, we conditionally expressed the human variant in the Drosophila external sense (ES) organ cell lineage using the GAL4-UAS system in conjunction with a temperature sensitive allele of the GAL80 repressor. The ES organs are mechanosensory bristles that develop from a single sensory organ precursor (SOP) cell which first divides into pIIa and pIIb daughter cells. These two cells undergo a series of asymmetric divisions, generating four terminal cell types: socket cell, shaft cell, sheath cell, and neuron. We have identified the period of development during pupal formation of Drosophila in order to observe the effects of CHMP2BIntron5 on our neural developmental model. We demonstrate that expression of CHMP2BIntron5 in the ES organ cell lineage at critical times during development causes cell fate transformation, most commonly observed as shaft cell to socket cell transformations. We also observe a pIIb to pIIa cell transformation, dependent upon the timing of CHMP2BIntron5 misexpression. The SOP cell lineage transformations are indicative of classical Notch signaling gain-of-function (GOF) phenotypes, and we subsequently see a partial recovery of shaft cells on the Drosophila notum when we remove a single copy of the Notch allele. This study of CHMP2B misexpression allowed us to gain a better understanding of CHMP2B’s role in cell signaling and eventually how mutant forms can give rise to FTD neurodegeneration.

Keywords

Dementia, CHMP2B, Fruit fly, misexpression

Available for download on Saturday, July 25, 2020

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