Decoding Development: Using Genetic Mutations to Understand Neurogenesis and Cell Fate

Abstract

Neurogenesis is the process by which new neurons are formed in the brain, and it is regulated by precise molecular and genetic programs that instruct the timing and order of neuronal birth. Mutations to genes that are essential for regulating the temporal pattern of cell divisions can disrupt neurogenesis, causing neurodevelopmental disease. One example is polymicrogyria (PMG), a congenital brain malformation that results in abnormal cortical folding and cortical disorganization due to altered neurogenesis and neuronal migration. Through functional investigations of PMG-causing mutations, we can characterize the molecular programs that govern cell proliferation in the human cortex. To this end, we functionally validated de novo missense variants found in Pannexin-1 (PANX1) in three individuals with severe PMG. PANX1 encodes a homo-heptameric ion channel that releases anions and ATP into the extracellular milieu. PMG-associated mutations in PANX1 were found to be gain of function, and their overexpression in mice and ferrets disrupted cell migration and cell fate through activity-dependent cell death. Through our findings, we establish a role for PANX1 in regulating neurogenesis by tuning the activity of progenitors and immature neurons. While in the neocortex, neurogenesis is known to end around the time of birth, there remains a debate in the literature as to whether neurogenesis continues throughout life in the human hippocampus. In mice, extensive research has demonstrated protracted neurogenesis in a region of the hippocampus known as the dentate gyrus (DG). Whether this phenomenon of adult hippocampal neurogenesis (AHN) occurs in humans is unclear. One of the major challenges in investigating AHN is the difficulty of identifying newborn (or newer born) neurons. To address this challenge, we used whole genome sequencing of single DG neurons to probe a cell’s genome as a “barcode” for its development. Every cell acquires somatic mutations in its genome as a result of cell division and aging processes. Discrete mutational patterns can emerge based on specific mutational processes, such as cell proliferation. Thus, by sequencing the DNA of single DG neurons, we assessed mutational signatures consistent with neurogenesis, strengthening the evidence for AHN.