Date of Award

1-1-2020

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

College/School/Department

Department of Biological Sciences

Content Description

1 online resource (xii, 117 pages) : illustrations (some color)

Dissertation/Thesis Chair

Paolo E Forni

Committee Members

Melinda Larsen, Prashanth Rangan, Christine K Wagner

Keywords

Axon Guidance, Cell Specification, Gene Regulation, Neuronal Identity, Transcription Factor, Vomeranasal Organ, Genetic transcription, Olfactory receptor genes, Mice as laboratory animals, Neurotransmitters, Developmental neurobiology, Nerves

Subject Categories

Cell Biology | Developmental Biology | Neuroscience and Neurobiology

Abstract

Developmental progression is driven by specific spatiotemporal gene expression, which give rise to consistently patterned organisms despite environmental and genetic variation. The specific activation of robust gene regulatory networks that define tissue structure and individual cellular identity are necessary for tissue and cell specific programs to be activated. Cellular specification is guided by the interplay of intrinsic and extrinsic signals at specific developmental timepoints. The molecular mechanisms underlying the acquisition and maintenance of individual cellular identity remains a fundamental question across biological systems. Understanding the regulatory networks controlling the acquisition of neuronal identity, diversity, and connectivity in the formation of a health and functional neuronal network is one of the major goals in developmental neuroscience. The mouse accessory olfactory system has emerged as an ideal model to study neuronal development, function, and connectivity. Within this system is the vomeronasal organ (VNO) where the cell bodies of the vomeronasal sensory neurons (VSNs) reside. The apical and basal populations VSNs, named for their spatial location in the vomeronasal epithelium (VNE), are produced by a common pool of progenitor cells, though they express different families of vomeronasal receptors (VRs), detect different sets of odorants, and mediate different social and reproductive behaviors in mice. My doctoral work has focused on examining the genetic differences between apical and basal VSNs and understanding the role and function of the transcription factor Tfap2e (AP-2ε), which is expressed by early immature neurons and selectively expressed by basal VSNs, in controlling or maintaining elements of the basal VSN program. To do this we examined the morphological and genetic phenotypes through AP-2ε loss-of-function, rescue, and ectopically induced expression. The work presented here reveals that AP-2ε is lineage specific for basal VSNs. We found that AP-2ε loss-of-function leads to a progressive loss of basal VSNs in part by the deviation of AP-2ε lineage traced VSNs towards a more apical-like identity. Conversely, I found that ectopic expression of AP-2ε in mature apical VSNs produces is sufficient to activate a large part of basal specific genes and to establishing neurons with hybrid apical-basal identity. My thesis work demonstrates that AP-2ε is a pivotal transcription factor in controlling the basal VSN genetic program and restriction of lineage inappropriate apical genes. Moreover, the cellular plasticity induced by ectopic AP-2ε expression in differentiated apical VSNs may suggest that AP-2ε has, like other members of the AP-2 family, pioneer factor activity.

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