The thalamus mediates a variety of important brain functions that are critical for
behavior and survival. A key feature that enables the thalamus to perform such diverse
functions is its parcellation into anatomically and functionally distinct groups of neurons
called nuclei. The purpose of this project was to identify the origin of neuronal diversity
within the thalamus by investigating the process of neurogenesis. During neurogenesis,
proliferating progenitor cells begin to divide asymmetrically to generate neurons. The
central hypothesis of the research presented herein is that thalamic organization requires
the appropriate number and types of neurons to be generated and that these critical
processes are regulated during neurogenesis. This work has characterized the different
types of progenitor cells present during thalamic neurogenesis. We confirmed the
existence of a special population of thalamic progenitor cells, intermediate (or basal)
progenitor cells, and identified transcription factors that regulate their formation and/or
maintenance. We also addressed the origin of distinct subtypes of neurons. The spatial
organization of thalamic progenitor cells into two distinct progenitor domains during
neurogenesis is thought to drive the formation of different subtypes of thalamic neurons.
Signaling molecules have been proposed to induce the formation of distinct progenitor
domains in numerous brain areas, including the thalamus. We provided a detailed
characterization of components of the Wnt/β-catenin-mediated transcriptional pathway
during thalamic neurogenesis. Based on the pattern of signaling activity, we
hypothesized that Wnt/β-catenin-mediated transcription has a function in forming the
two progenitor domains during thalamic neurogenesis. Using conditional genetic manipulations of β-catenin, we found that β-catenin-mediated transcription is required
for the specification of thalamic progenitor domains. Furthermore, we found that the
Wnt/β-catenin signaling pathway functions in parallel with the sonic hedgehog (Shh)
signaling pathway, which had been previously shown to specify thalamic progenitor
identity in an opposing manner, by independently regulating transcriptional networks in
thalamic progenitor cells. Collectively, the process of neurogenesis involves the
generation of the correct number of neurons by regulating asymmetric progenitor
divisions and generation of appropriate neuronal subtypes through the functions of
signaling pathways and transcriptional networks. These mechanisms provide a broad
map for the generation and positioning of appropriate types of neurons in the correct
locations within the thalamus.
University of Minnesota Ph.D. dissertation. June 2012. Major:Neuroscience. Advisor: Associate Professor Yasushi Nakagawa, M.D., Ph.D., 1 computer file (PDF); ix, 161 pages.
Bluske, Krista K..
Investigating neurogenesis and cell type specification in the mammalian thalamus..
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