Transcription Factor Expression In The Central Nervous System PDF Download

The central nervous system is the most complex and highly organized tissue in animals; composed of thousands of neurites connected in specific and highly reproducible ways. My thesis research has focused on the generation of neuronal diversity: specifically how neurons adopt individual, often unique, identities. Work in many labs has revealed that a large set of transcription factors act in combinatorial manner to specify the fate of individual neurons or small groups of neurons. However, in most cases, it remains unclear how individual or specific combinations of transcription factors directly control the terminal differentiation of neurons via the regulation of different genes, such as neurotransmitters. My thesis work has focused on the identification and characterization of new members of the combinatorial code of transcription factor and on initial attempts to link these transcription factors to the expression and activity of genes that contribute directly to neuronal differentiation. In chapter 2, I describe the identification and characterization of Dbx, a homedomain-containing transcription factor, expressed in a mixture of progenitor cells and a subset of GABAergic interneurons. I show that Dbx is expressed in many interneurons that are sibling to motor neurons, and that Dbx is required to promote the development of these interneurons via cross-repressive interactions with Eve and Hb9, which are expressed in the sibling motor neurons. In chapter 3, I detail the identification of FoxD, a transcription factor that is positively regulated by the homeodomain-containing transcription factor Hb9 in the Drosophila CNS. FoxD is expressed in a subset of Hb9 positive neurons and also in all octopaminergic neurons in the Drosophila embryonic CNS. I have identified the enhancers that drive expression in these neurons and have recently generated two mutant alleles of foxD. Loss of foxD appears to result in hyperactivity, which is most pronounced in males. As octopamine is the fly equivalent of norepinephrine, these results suggest that FoxD may function in specific cells to regulate the synthesis and release of octopmaine. Thus, my thesis has identified two members of the combinatorial code of transcription factors that govern neuronal identity. In addition, it has begun to place the functions of these genes within the genetic regulatory hierarchy of this code and started to link the function of individual transcription factors to the regulation of terminal differentiation genes and animal behavior.