Dissertation
Novel roles of the Type I bHLH proteins Daughterless/Tcf4 in postmitotic neurons of the central nervous system
Doctor of Philosophy (Ph.D.), Drexel University
May 2015
DOI:
https://doi.org/10.17918/etd-7211
Abstract
Neurogenesis, the production of neuronal and glial lineages from undifferentiated precursor cells, is a critical step for embryonic neurodevelopment. Later in development, these cells become postmitotic, attaining cellular senescence and cease to divide. Proneural proteins of Class I/II Basic helix-loop-helix (bHLH) proteins are a large family of evolutionarily conserved transcription factors that have well-established roles in neurogenesis and neural differentiation across multiple species. Historically, our understanding of the function of class I/II transcription factors has largely focused on their function as regulators of neurogenesis, however their role in post-mitotic neurons remain unclear. The major objective of this work was to explore the role of bHLH transcription factor Daughterless (Da, Tcf4 in mammals) in postmitotic, differentiated motor neurons. The first set of studies, Chapter II, demonstrates that Da is expressed in postmitotic neurons in Drosophila melanogaster and is required to restrict synaptic growth and axonal arborization at the Drosophila neuromuscular junction (NMJ). We used bioinformatic tools to identify candidate genes whose transcription is regulated by Da and have identified and validated that cell-adhesion molecule neurexin is required for Da-mediated restriction of synaptic growth. In the second set of studies, Chapter III, we show that Tcf4 is also expressed in mouse brain postmitotic neurons, and mouse Tcf4 also functions to restrict synaptogenesis in mouse neurons. We outline a novel role for Class I proteins Da/Tcf4 outside of their established roles in neurogenesis, and conclude a novel function of class I bHLH proteins in neural function. In all, our studies are important to human health because mutations in Tcf4 have been linked to autism spectrum disorders and schizophrenia. Our integrative approach will provide a paradigm for how class I bHLH proteins can control different target genes in postmitotic neurons and are critical building models to better understand the etiology of these diseases and design possible therapeutic.
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Details
- Title
- Novel roles of the Type I bHLH proteins Daughterless/Tcf4 in postmitotic neurons of the central nervous system
- Creators
- Mitchell R. D'Rozario - DU
- Contributors
- Daniel Marenda (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Biology; College of Arts and Sciences; Drexel University
- Other Identifier
- 7211; 991014632398504721