Stacey Peek
“Cellular and Molecular Mechanisms of Akirin2 Function in Maturing Neurons”
During cortical development, neurons exit the cell cycle and undergo terminal differentiation. At this time, 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 them 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 the mechanisms controlling neuronal gene expression, this doctoral work elucidates molecular mechanisms of the nuclear protein, Akirin2, in neuron maturation and gene regulation.
Initial studies on the Akirin family of proteins demonstrated that Akirin2 is essential for development. In several cellular contexts Akirin2 binds to transcription factors and chromatin remodeling complexes to regulate gene expression patterns. While previous work shows that Akirin2 regulates proliferation and differentiation in the immune system, myogenesis, and tumorogenesis, until recently, it had never been studied in the brain. In a mouse model of cortical development, the Weiner lab previously demonstrated that Akirin2 is essential for corticogenesis as its loss in cortical progenitor cells resulted in cortical agenesis due to progenitor exit from the cell cycle, early differentiation, and massive apoptosis. While these studies demonstrated a critical need for Akirin2 during cortical development, the mechanisms of Akirin2 in this context remained unclear. Furthermore, early neuronal death prevented the study of Akirin2 in maturing neurons.
This dissertation shows that neurons decrease their Akirin2 expression during postnatal development, yet it remains critical for maintaining healthy neurons. Loss of Akirin2 in a large subset of excitatory cortical neurons resulted in cortical atrophy and neurodegeneration by a programmed cell death mechanism called necroptosis. Transcriptomic analyses of Akirin2-null cortical progenitors and Akirin2-null neurons revealed an enrichment of targets of the tumor suppressor protein, p53, a well-known regulator of proliferation and death. Additionally, decreased p53 expression rescued Akirin2-null neurons from death. Together, these data implicate Akirin2 loss with gene dysregulation and neurodegeneration 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 caused by Akirin2 loss in multiple biological systems.
