A temporally-restricted pattern of endothelial cell collagen 4 alpha 1 expression during embryonic development determined with a novel knockin Col4a1-P2A-eGFP mouse line.

Classical collagen type IV comprising of a heterotrimer of two collagen IV alpha 1 chains and one collagen IV alpha 2 chain is the principal type of collagen synthesized by endothelial cells (EC) and is a major constituent of vascular basement membranes. In mouse and man, mutations in genes that encode collagen IV alpha 1 and alpha 2 result in vascular dysfunction. In addition, mutations in genes that encode the Ephrin receptor B4 (EPHB4) and the p120 Ras GTPase-activating protein (RASA1) that cause increased activation of the Ras mitogen-activated protein kinase (MAPK) signaling pathway in EC result in vascular dysfunction as a consequence of impaired export of collagen IV. To understand the pathogenesis of collagen IV-related vascular diseases and phenotypes it is necessary to identify at which times collagen IV is actively synthesized by EC. For this purpose, we used CRISPR/Cas9 targeting in mice to include immediately after the terminal Col4a1 codon a sequence that specifies a P2A peptide followed by enhanced green fluorescent protein (eGFP). Analysis of eGFP expression in Col4a1-P2A-eGFP mice revealed active embryonic EC synthesis of collagen IV alpha 1 through mid to late gestation followed by a sharp decline before birth. These results provide a contextual framework for understanding the basis for the varied vascular abnormalities resulting from perturbation of EC expression and export of functional collagen IV.

Lifespan extension in female mice by early, transient exposure to adult female olfactory cues.

Several previous lines of research have suggested, indirectly, that mouse lifespan is particularly susceptible to endocrine or nutritional signals in the first few weeks of life, as tested by manipulations of litter size, growth hormone levels, or mutations with effects specifically on early-life growth rate. The pace of early development in mice can also be influenced by exposure of nursing and weanling mice to olfactory cues. In particular, odors of same-sex adult mice can in some circumstances delay maturation. We hypothesized that olfactory information might also have a sex-specific effect on lifespan, and we show here that the lifespan of female mice can be increased significantly by odors from adult females administered transiently, that is from 3 days until 60 days of age. Female lifespan was not modified by male odors, nor was male lifespan susceptible to odors from adults of either sex. Conditional deletion of the G protein Gαo in the olfactory system, which leads to impaired accessory olfactory system function and blunted reproductive priming responses to male odors in females, did not modify the effect of female odors on female lifespan. Our data provide support for the idea that very young mice are susceptible to influences that can have long-lasting effects on health maintenance in later life, and provide a potential example of lifespan extension by olfactory cues in mice.

The environment that animals are exposed to early in life can influence their subsequent rate of development, reproduction and aging. Experiments done in rodents have shown that social stimuli such as odours from the same sex or opposite sex individuals can affect the age at which sexual maturity is reached. Variations in age of sexual maturity are directly correlated with median lifespans of mice, with strong associations observed between later sexual maturity and longer lifespans in female mice. Detailed experiments exposing female or male mice to scents from mice of the same or another sex strongly suggest that growing up smelling the same sex can delay sexual maturity, while scents from another sex can hasten it. Interestingly, mice that lacked the cells that sense odours do not change their age of sexual maturity in response to scents from the opposite sex. This ability to steer one's developmental timeline depending on environmental cues may allow animals to prepare for future environments. But can it also influence an animal's lifespan? To answer this question, Garratt et al. observed the lifespans of female and male mice under different conditions. Mice were exposed to same-sex or other-sex odours, in the form of urine or soiled bedding, from day 3 to day 60 of their lives. The results showed that female mice exposed to odours from other females exhibited an increased lifespan, as compared to those not exposed to scents, while those exposed to odours from males did not show any change in their lifespan. In striking contrast, male mice exposed to odours from either sex showed no variation in their lifespans. The impairment of a particular type of odour-sensing neuron in mice did not change these results, making it likely that another neuron type is responsible for the changes in lifespan observed in the female mice. These experiments elegantly demonstrate that exposure to certain sensory information, in this case scent, can change how long mammals live. While similar effects involving smells are unlikely to influence lifespan in humans, it is possible that other types of sensory information affect our health and how we age.