Temporal control of the termination of neurogenesis

About This Grant

Abstract. Why can’t adult mammalian brains fully regenerate after damage or degeneration? The primary reason lies in their limited capacity for neurogenesis. In adult mice, neurogenesis occurs slowly and only in the olfactory bulb and the hippocampus. This is a stark difference from embryonic stages, where rapid neurogenesis occurs throughout all brain regions. The source behind this rapid embryonic neurogenesis is the embryonic neural stem cells (NSCs), also known as radial glia. Shortly after birth, however, these cells “disappear” by retracting their long radial processes and transforming into other cell types. Consequently, neurogenesis is terminated throughout the majority of the central nervous system (CNS). Similar to mice, radial glia in humans rapidly generate neurons during embryonic development and disappear postnatally, leading to the termination of neurogenesis. How do NSCs keep time and shut down neurogenesis on a predictable schedule? What is the molecular logic underlying the disappearance of radial glia? These questions remain unanswered. Temporal control of postnatal termination of neurogenesis is one of the major knowledge gaps in brain development and this lack of understanding presents a significant bottleneck in stem cell therapy development. Currently, experimental NSC transplantation therapies fail to generate sufficient numbers of neurons to significantly improve disease outcome and, consequently, there is no Food and Drug Administration-approved NSC therapy yet. Investigating the regulation of the termination of neurogenesis in the developing brain will reveal novel molecular targets for maintaining or expanding the duration of neurogenesis of transplanted NSCs, which can be targeted for the development of next generation NSC therapies. NSC therapies with enhanced neurogenesis capacity could transform the treatment landscape of a broad range of neurological disorders including stroke and neurodegeneration. Here, we propose to investigate the temporal control of the postnatal termination of neurogenesis and the disappearance of embryonic radial glia. A serendipitous discovery led us to study the role of PR-domain containing 16 (Prdm16), a histone methyltransferase, in postnatal NSCs. Our preliminary studies show that genetic deletion of Prdm16 from NSCs leads to the persistence of radial glia in the adult NSC niche and prolonged postnatal neurogenesis in the cerebral cortex. Based on these findings, we hypothesize that Prdm16 promotes the postnatal disappearance of embryonic radial glia and the termination of cortical neurogenesis. In Aim 1, we will determine the role of Prdm16 in regulating the fate and function of quiescent and activated NSCs. In Aim 2, we will identify the downstream mechanisms through which Prdm16 regulates the postnatal disappearance of embryonic radial glia and neurogenesis termination. In Aim 3, we will target the Prdm16-Vcam1 pathway to promote post-stroke neurogenesis.