The roles of canonical Wnt signaling and Lef1 in zebrafish hypothalamic neuronal development

Lee, J.E.
Ph.D. Thesis : 146p (Thesis)
Registered Authors
Lee, Ji Eun
Biological sciences, Hypothalamus, LEF1, Neuronal development, Wnt
MeSH Terms
The hypothalamus, a vital brain structure controlling body homeostasis, develops through processes that include induction, patterning, neurogenesis, and neuronal differentiation. These processes are tightly regulated by several growth factors such as Nodal, Hedgehog (Hh), and Wnt, which induce specific downstream signaling events during each step of hypothalamus development. This dissertation is focused on the role of Wnt signaling and Lef1 during hypothalamic neurogenesis. In Chapter 1, I introduce the anatomy, function, and development of the hypothalamus. I also review the functions of the components, including TCF/LEF transcription factor family members, of the Wnt signaling pathway during embryonic development. Finally, I summarize the functions of Wnt and Lef1 during development of the brain including the hypothalamus, and introduce a noncomplementation mutant screen in zebrafish.
In Chapter 2, I have investigated the role of canonical Wnt signaling through Lef1 during hypothalamic neurogenesis using lef1- and wnt8b-loss-of-function studies. I found that Wnt8b acts as an upstream regulator controlling lef1-mediated neurogenesis in the posterior hypothalamus. Furthermore, the results of these studies demonstrate that Lef1 protein binds to the sox3 gene regulatory region, and suggest that a conserved Wnt-Sox molecular pathway might be a common mechanism in regulation of CNS neurogenesis in vertebrates.
In Chapter 3, to determine unknown hypothalamic neuronal identities, further roles of Lef1 during hypothalamic neuronal differentiation, as well as hypothalamic neuronal anatomy have been investigated. I report that Lef1-dependent GABAergic neurons are generated through the conserved zash1a-dlx-gad gene pathway in the hypothalamus.
In Chapter 4, I have performed a noncomplementation screen to find a lef1 mutant. Putative mutant #2 (PMT#2, assigned allele number zd1), originally considered as a lef1 mutant candidate, has been characterized in several ways. The data collectively suggest that PMT#2zd1 (hereafter referred to as zd1) might be a mutation in another gene involved in hypothalamic neurogenesis.
In Chapter 5, I discuss the roles of Wnt signaling through Lef1 and Sox3 throughout hypothalamus development. I also discuss several approaches to obtain a lef1 mutant in the future and speculate on possible target genes of Lef1 involved in regulation of hypothalamic neurogenesis.
Errata / Notes
Ph.D. Thesis, Department of Neurobiology and Anatomy, University of Utah
Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes