Reduction of Paraoxonase Expression Followed by Inactivation across Independent Semiaquatic Mammals Suggests Stepwise Path to Pseudogenization.

Convergent adaptation to the same environment by multiple lineages frequently involves rapid evolutionary change at the same genes, implicating these genes as important for environmental adaptation. Such adaptive molecular changes may yield either change or loss of protein function; loss of function can eliminate newly deleterious proteins or reduce energy necessary for protein production. We previously found a striking case of recurrent pseudogenization of the Paraoxonase 1 (Pon1) gene among aquatic mammal lineages-Pon1 became a pseudogene with genetic lesions, such as stop codons and frameshifts, at least four times independently in aquatic and semiaquatic mammals. Here, we assess the landscape and pace of pseudogenization by studying Pon1 sequences, expression levels, and enzymatic activity across four aquatic and semiaquatic mammal lineages: pinnipeds, cetaceans, otters, and beavers. We observe in beavers and pinnipeds an unexpected reduction in expression of Pon3, a paralog with similar expression patterns but different substrate preferences. Ultimately, in all lineages with aquatic/semiaquatic members, we find that preceding any coding-level pseudogenization events in Pon1, there is a drastic decrease in expression, followed by relaxed selection, thus allowing accumulation of disrupting mutations. The recurrent loss of Pon1 function in aquatic/semiaquatic lineages is consistent with a benefit to Pon1 functional loss in aquatic environments. Accordingly, we examine diving and dietary traits across pinniped species as potential driving forces of Pon1 functional loss. We find that loss is best associated with diving activity and likely results from changes in selective pressures associated with hypoxia and hypoxia-induced inflammation.

The anti-viral immune response of the adult host robustly modulates neural stem cell activity in spatial, temporal, and sex-specific manners.

Viruses induce a wide range of neurological sequelae through the dysfunction and death of infected cells and persistent inflammation in the brain. Neural stem cells (NSCs) are often disturbed during viral infections. Although some viruses directly infect and kill NSCs, the antiviral immune response may also indirectly affect NSCs. To better understand how NSCs are influenced by a productive immune response, where the virus is successfully resolved and the host survives, we used the CD46+ mouse model of neuron-restricted measles virus (MeV) infection. As NSCs are spared from direct infection in this model, they serve as bystanders to the antiviral immune response initiated by selective infection of mature neurons. MeV-infected mice showed distinct regional and temporal changes in NSCs in the primary neurogenic niches of the brain, the hippocampus and subventricular zone (SVZ). Hippocampal NSCs increased throughout the infection (7 and 60 days post-infection; dpi), while mature neurons transiently declined at 7 dpi and then rebounded to basal levels by 60 dpi. In the SVZ, NSC numbers were unchanged, but mature neurons declined even after the infection was controlled at 60 dpi. Further analyses demonstrated sex, temporal, and region-specific changes in NSC proliferation and neurogenesis throughout the infection. A relatively long-term increase in NSC proliferation and neurogenesis was observed in the hippocampus; however, neurogenesis was reduced in the SVZ. This decline in SVZ neurogenesis was associated with increased immature neurons in the olfactory bulb in female, but not male mice, suggesting potential migration of newly-made neurons out of the female SVZ. These sex differences in SVZ neurogenesis were accompanied by higher infiltration of B cells and greater expression of interferon-gamma and interleukin-6 in female mice. Learning, memory, and olfaction tests revealed no overt behavioral changes after the acute infection subsided. These results indicate that antiviral immunity modulates NSC activity in adult mice without inducing gross behavioral deficits among those tested, suggestive of mechanisms to restore neurons and maintain adaptive behavior, but also revealing the potential for robust NSC disruption in subclinical infections.

Neural Stem Cells: What Happens When They Go Viral?

Viruses that infect the central nervous system (CNS) are associated with developmental abnormalities as well as neuropsychiatric and degenerative conditions. Many of these viruses such as Zika virus (ZIKV), cytomegalovirus (CMV), and herpes simplex virus (HSV) demonstrate tropism for neural stem cells (NSCs). NSCs are the multipotent progenitor cells of the brain that have the ability to form neurons, astrocytes, and oligodendrocytes. Viral infections often alter the function of NSCs, with profound impacts on the growth and repair of the brain. There are a wide spectrum of effects on NSCs, which differ by the type of virus, the model system, the cell types studied, and the age of the host. Thus, it is a challenge to predict and define the consequences of interactions between viruses and NSCs. The purpose of this review is to dissect the mechanisms by which viruses can affect survival, proliferation, and differentiation of NSCs. This review also sheds light on the contribution of key antiviral cytokines in the impairment of NSC activity during a viral infection, revealing a complex interplay between NSCs, viruses, and the immune system.