The medial ganglionic eminence (MGE) is a progenitor domain in the subpallium that produces both locally-projecting interneurons which undergo tangential migration in structures such as the cortex as well as long-range projection neurons that occupy subcortical nuclei. Very little is known about the transcriptional mechanisms specifying the migratory behavior and axonal projection patterns of these two broad classes of MGE-derived neurons. In this study, I identify St18 as a novel transcriptional determinant specifying projection neuron fate in the MGE lineage. St18 is transiently expressed in the MGE subventricular zone (SVZ) and mantle, and I assessed its function using an ES cell-based model of MGE development. Induction of St18 is sufficient to direct ES-derived MGE neurons to adopt a projection neuron-like identity as defined by migration and morphology. Through gene expression analysis I identified a downstream effector of St18, Cbx7, which is a component of Polycomb repressor complex 1.
I find that Cbx7 is essential for projection neuron-like migration and is not involved in St18-mediated projection neuron-like morphology. Using genetic loss-of-function in mice, I find that St18 is required for the production of globus pallidus pars externa (GPe) prototypic projection neurons. Single cell RNA sequencing revealed that St18 regulates MGE output of specific neuronal populations: in the absence of St18, I observe a large expansion of cortical interneurons at the expense of putative GPe neurons. I also find that, following St18 genetic loss of function, mouse walk cycles are disrupted downstream of a loss of a critical neuronal projection from the GPe to the sub thalamic nucleus (STN). These results characterize a novel transcriptional determinant that directs GPe prototypic projection neuron identity within the MGE lineage. Further, I have identified a downstream target of St18, Cbx7, which regulates only the migratory behavior of long-range projection neurons, suggesting that specific features of MGE projection neuron identity may be governed in a compartmentalized fashion by distinct transcriptional modules downstream of St18. I’ve also demonstrated the role of the GPe PV+ prototypic neurons in the production and maintenance of mouse locomotor gait.
| Identifer | oai:union.ndltd.org:columbia.edu/oai:academiccommons.columbia.edu:10.7916/d8-yeqs-hj91 |
| Date | January 2021 |
| Creators | Nunnelly, Luke Frazier |
| Source Sets | Columbia University |
| Language | English |
| Detected Language | English |
| Type | Theses |
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