GSBS Dissertations and Theses

Approval Date

9-20-2016

Document Type

Doctoral Dissertation

Academic Program

Neuroscience

Department

Department of Neurobiology; Budnik Lab

First Thesis Advisor

Vivian Budnik

Keywords

Drosophila melanogaster, Premature Aging; Neuromuscular Junction, Neurons, Synapses, Nuclear Envelope

Subjects

Dissertations, UMMS; Drosophila melanogaster; Aging, Premature; Neuromuscular Junction; Neurons; Synapses; Nuclear Envelope

Abstract

Development and aging, two fundamental aspects of life, remain key biological processes that researchers try to understand. Drosophila melanogaster, thanks to its various merits, serves as an excellent model to study both of these processes. This thesis includes two parts. In the first part, I discuss our finding that the presynaptic neuron controls a retrograde signaling pathway by releasing essential components via exosomes. During synaptic development, postsynaptic cells send retrograde signals to adjust the activity and growth of presynaptic cells. It remains unclear what the mechanism is which triggers the release of retrograde signals; and how presynaptic cells are involved in this signaling event. The first part of this thesis demonstrates that a retrograde signal mediated by Synaptotagmin4 (Syt4) depends on the anterograde delivery of Syt4 protein from the presynaptic neuron to the muscle compartment likely through exosomes. This trans-synaptic transfer of Syt4 is required for the retrograde control of activity-dependent synaptic growth at the Drosophila larval neuromuscular junction.

In the second part of this thesis, I talk about our discovery that the disruption of nuclear envelope (NE) budding, a novel RNA export pathway, is linked to the loss of mitochondrial integrity and premature aging in Drosophila. We demonstrate that several transcripts, which are essential for mitochondrial integrity and function, use NE-budding for nuclear export. Transgenic Drosophila expressing a LamC mutation modeling progeroid syndrome (PS), a premature aging disorder in humans, displays accelerated aging-related phenotypes including progressive mitochondrial degeneration as well as decreased levels of a specific mitochondrial transcript which is normally enriched at NE-budding site. The PS-modeled LamC mutants exhibit abnormal lamina organization that likely disrupts the egress of these RNAs via NE-budding. These results connect defective RNA export through NE-budding to progressive loss of mitochondrial integrity and premature aging in Drosophila.

Comments

This dissertation includes 2 videos that are available under "Additional Files."

DOI

10.13028/M2MK5G

Rights and Permissions

Copyright is held by the author, with all rights reserved.

Movie 1.mov (1410 kB)
Movie 1. Escape response in control flies. Movie showing the flight behavior of 21-day old control and LamC-WT, lamC/+ flies.

Movie 2.mov (1898 kB)
Movie 2. Escape response in PS-modeled LamC flies. Movie depicting flight behavior of 4-day and 21-day old LamC-E174K, lamC/+ flies.

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