Date of Award

1-6-2017

Degree Type

Closed Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Walter Walthall

Second Advisor

Nancy Forger

Third Advisor

Casonya Johnson

Fourth Advisor

Patrick McGrath

Abstract

Development of the nervous system is a highly organized process that utilizes genetic mechanisms conserved across the animal kingdom. Components of the nervous system such as inhibitory GABAergic neural networks are common among most multicellular animals. The nematode Caenorhabditis elegans, utilizes similar genetic pathways to that of mice and humans to develop its GABAergic neural networks. These GABAergic neural networks are composed of two types of GABAergic motor neurons: the VD and DD sub-classes. The GABAergic differentiation of both these sub-classes requires the conserved transcription factor, Pitx/UNC-30. The VD sub-class is differentiated from the DD motor neurons by the expression of another transcription factor, COUP TFII/UNC-55. The transcriptional mechanisms regulating the expression of Pitx/UNC-30 and Coup TFII are unknown. We sought to determine how Pitx/UNC-30 and COUP TF-II/UNC-55 were transcriptionally regulated in an attempt to understand how mechanisms of GABAergic fate specification and class specification may be connected. We hypothesized there would be different mechanisms regulating the GABAergic differentiation and sub-class specification of the two sub-classes of GABAergic motor neurons. To test this, we dissected the transcriptional mechanisms responsible for the expression of Pitx/UNC-30 and COUP TFII/UNC-55. We found that different isoforms of the Hox cofactor Meis/UNC-62 stabilize and activate the expression of UNC-55. Furthermore, we conclude that Pitx/UNC-30 expression is regulated differently between the two motor neuron sub-classes by Meis/UNC-62, Hox-B7/MAB-5 and NeuroD/CND-1, each of which are vital to the development of different components of the nervous system in vertebrates. Our findings suggest that the GABAergic identity and the sub-class specification of neurons are under the control of multiple conserved transcription factors responsible for neuron fate determination and post mitotic identities.

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