Genetic mechanisms of thalamic nuclei specification and the influence of thalamocortical axons in regulating neocortical area formation.

摘要

Sensory information from the periphery is essential for all animal species to learn, adapt, and survive in their environment. The thalamus, a critical structure in the diencephalon, receives sensory information such as vision, somatosensation, and audition from the periphery, and then relays this information to the primary visual (V1), somatosensory (S1), and auditory (A1) areas in the neocortex, respectively. Architecturally, the thalamus is parcellated into more than two dozen cell aggregates called nuclei, each of which sends long distance projections called thalamocortical axons (TCAs) to innervate different areas of the neocortex in a topographic manner. Conversely, different areas of the neocortex also project corticothalamic axons (CTAs) back to each thalamic nucleus in a reciprocal manner. This reciprocal connection between the thalamus and neocortex is thought to be critically important for synchronizing the neuronal networks between different parts of the brain in order to generate learned behaviors in animals. To date, however, very little is known about the mechanisms that govern thalamic development, particularly nuclei specification and formation, or about the influence of TCAs in regulating the development of the neocortex into functionally distinct areas.;Using the mouse as a model, the goal of my thesis work was three-folds. First, I described in detail the molecular profile of thalamic progenitor cells by characterizing the expression patterns of a number of basic-helix-loop-helix (bHLH) (Mash1, Ngn1/2, Olig2, Olig3) and homeodomain (HD) (Dbx1, Nkx2.2) transcription factors, all of which have been shown to be important for specifying neuronal diversity in other parts of the central nervous system (CNS). I then traced the lineage of thalamic progenitor cells that express each of the bHLH or HD transcription factors using transgenic reporter mice to determine the progenitor origin and relative migration path of neurons of the various thalamic nuclei. Second, I investigated how the expression patterns of the transcription factors are regulated by the morphogen Shh, which is expressed in cells that border the embryonic thalamus rostrally and ventrally, and the developmental consequences of altering the expression patterns of these transcription factors early in the mouse embryo on thalamic nuclei specification. Finally, I discovered that the size of the principle sensory nuclei, the dorsal lateral geniculate (dLG), which projects TCAs specifically to V1, is significantly increased or decreased when the level of Shh signaling is elevated or reduced in thalamic progenitor cells, respectively. I then assessed how these changes to the size of dLG can affect the size and shape of the primary visual area (V1) later in postnatal development. The culmination of my thesis research has shown that the fate of cells in the CNS is specified by both intrinsic and extrinsic mechanisms, and the alteration of the development of one brain area can have a non-cell autonomous impact on the development and differentiation of another.