Molecular Regulation of Neurogenesis in Health and Disease

Abstract

The molecular mechanisms that fine-tune neurogenesis in the embryo shape the structure and function of the mature brain. Despite this, the regulation of this process is poorly understood and requires investigation in health and disease. The medial ganglionic eminence (MGE) is a transitory structure that forms during embryonic stages of development and contains a diverse population of neural progenitor cells. Unique genetic, spatial, and temporal programs regulate the cell-cycle properties of MGE progenitors, which facilitates the generation of striatal and cortical interneurons. The ETS transcription factor Etv1/Er81 is expressed in a subpopulation of striatal and cortical interneurons that are derived from the MGE, and it controls key stages of differentiation, migration, axonogenesis and neuron activity. Furthermore, studies into cancer cell-lines have shown Etv1/Er81 regulates proliferation and metastasis. Despite this, and that Etv1/Er81 is expressed in a subpopulation of MGE progenitor cells, no study has investigated whether Etv1/Er81 regulates MGE proliferation, and if it controls the subsequent developmental trajectory of interneurons. In chapter 1 of this thesis, we first investigated the spatial distribution pattern of Etv1/Er81 in progenitors of the MGE across embryonic development. We show that Etv1/Er81 is expressed throughout the MGE and is enriched in ventral regions. Conditional ablation of Etv1/Er81 from the MGE leads to a shift in the spatial distribution of progenitors. This is coupled to a reduction in proliferation both within cells that have lost Etv1/Er81 expression, and the wider MGE network. Together, we show that Etv1/Er81 expression directly facilitates the proliferation of MGE progenitors. In chapter 2, we examine the effect perturbing Etv1/Er81 in MGE cells has on the final number, distribution, and molecular identity of cortical and striatal interneurons. We reveal that conditional ablation of Etv1/Er81 from the MGE leads to a substantial loss of MGE-derived cells. Etv1/Er81 deletion at embryonic day (E) 12 leads to a substantial reduction in the number of MGE-derived cells and an associated loss of parvalbumin interneurons. We show that this phenotype likely arises from a loss of cells born at E15, the peak period of parvalbumin neurogenesis. Ablating Etv1/Er81 later during MGE development (E15) also leads to a loss of MGE-derived interneurons, however it does not perturb the final molecular identity of cells. On the other hand, specific ablation of Etv1/Er81 from postmitotic MGE cells alters identity, but not the number of MGE-derived interneurons, suggesting that perturbing Etv1/Er81 in progenitor cells reduces proliferation and subsequent cell-number in adult circuitry. In the final chapter, we complete an investigation into why the developmental course of interneurons is altered in autism spectrum disorders (ASD). We hypothesise that it results from premature maturation of the MGE and associated changes to proliferation. We present that the MGE prematurely develops in the ASD condition which is coupled to changes to the proliferative dynamics of progenitors. We show that this leads to an overproduction of interneurons which persists to early postnatal stages of interneuron development. Overall, we describe an innate molecular mechanism which critically regulates neurogenesis and show that the proliferative dynamics of progenitors are disrupted in ASD pathology. Show more