Cellular and molecular mechanisms of Akirin2 function in maturing neurons

During cortical development, neurons exit the cell cycle to undergo terminal differentiation. At this time, temporally- and spatially- regulated gene expression patterns guide developing neurons to become highly specialized cells with specific characteristics and functions. Once these gene expression patterns are established, neurons must maintain these patterns or risk losing their identity, proper function, and death. Gene dysregulation in terminally differentiated neurons can therefore result in cognitive impairment and neurodegeneration. To better understand neuronal gene regulation with an overall goal of informing therapeutics, this doctoral work elucidates cellular functions and molecular mechanisms of the nuclear protein, Akirin2, in neuron maturation and gene regulation. Initial studies on the Akirin family of proteins, which consist of one invertebrate orthologue and two mammalian orthologues (Akirin1 and Akirin2), demonstrated that Akirin2 is the mammalian homologue essential for development. In several cellular contexts Akirin2 binds to transcription factors and chromatin remodeling complexes, recruiting this regulatory machinery to Akirin2-dependent gene promoters. In this manner, Akirin2 regulates gene expression in immune system activation, myogenesis, and tumorigenesis. However, until recently it had never been studied in the brain. In a mouse model of cortical development, our lab recently demonstrated that Akirin2 is essential for corticogenesis as its loss in cortical progenitor cells resulted in aberrant cell cycle exit, early neuronal differentiation, and massive apoptosis. As a result, the mice were born without a cortex and died shortly after birth. While these studies demonstrated a critical need for Akirin2 during cortical development, the mechanisms of Akirin2 in this context remained unclear, and early neuronal death prevented the study of Akirin2 in maturing neurons. In this dissertation, I show that although neurons decrease their Akirin2 expression during postnatal development, it continues to play a critical role in maintaining healthy postnatal neurons. Loss of Akirin2 in a large subset of excitatory cortical neurons resulted in cortical atrophy and neurodegeneration with convergent evidence pointing to a programmed cell death mechanism called necroptosis. Transcriptomic analysis suggested that Akirin2 critically regulates cell cycle genes in postmitotic neurons. Furthermore, comparing transcriptomes from an Akirin2-null cortical progenitor mouse model and transcriptomes from mouse cortices with many Akirin2-null neurons revealed an enrichment of targets of the tumor suppressor protein, p53, a well-known regulator of proliferation and death. Further supporting a role for p53, decreased p53 expression (through deletion of a single Trp53 allele) rescued death in Akirin2-null neurons. Together, these data implicate the loss of Akirin2 with gene dysregulation that results in neurodegeneration in postnatal neurons and provide evidence for p53 as a novel Akirin2 interactor. This discovery also suggests that the pleiotropic functions of p53 may underlie the wide array of phenotypes seen in multiple Akirin2-null cells across several biological systems.