Monko, Timothy2022-02-152022-02-152021-10https://hdl.handle.net/11299/226379University of Minnesota Ph.D. dissertation. 2021. Major: Neuroscience. Advisor: Yasushi Nakagawa. 1 computer file (PDF); 127 pages.The mammalian neocortex is composed of diverse types of neurons that are sequentially generated during embryonic development and are arranged in an orderly manner across layers. In the adult neocortex, the distribution and density of each neuronal type differ across the cortex. In primary sensory cortex—visual, somatosensory, and auditory—neurons that reside in layer 4 are targeted by axons from corresponding principal sensory nuclei of the thalamus. Synaptic activity of these thalamocortical axons are known to shape cellular organization, characteristic morphology, and patterns of gene expression of layer 4 neurons in postnatal sensory cortex. Even though experiments nearly half a century ago found evidence for this thalamocortical axon based extrinsic regulation of the mammalian neocortex, most scientists today attribute the specification of sensory cortex to be driven by intrinsic gene regulatory mechanisms. However, whether these axons influence earlier stages of development, including neurogenesis and neuronal fate specification is poorly understood. We first found that thalamocortical axons arrive in the cortex during the early period of superficial layer neurogenesis. Analysis of mutant mice lacking the majority of thalamocortical axons showed a decreased number of superficial layer neurons in primary visual and somatosensory areas, but not in motor areas, at early postnatal stages. During embryonic development, lack of thalamocortical axons decreased the number and division of radial glia and intermediate progenitor cells in a sensory area-specific manner. Cell fate analysis using pulse-labeling of progenitor cells with a thymidine analog revealed that thalamocortical axons are required for proper specification of superficial layer neurons towards layer 4. Further evidence revealed that this role of thalamocortical axons on cell fate is exerted as early as neonatal stages, demonstrating that these axons are required for the proper number of layer 4 neurons to be generated and specified in primary sensory areas even before mature synaptic input. We found that these area-specific roles are in part played by the thalamus-derived molecule, VGF. In summary, our study provides a mechanism by which afferent input to the neocortex from the thalamus complements the intrinsic program of early cortical development, allowing the sequential generation of diverse neuron types in an area-specific manner.enCell FateNeocortexNeurogenesisThalamocorticalThesis or Dissertation