Most mammals maintain their body temperature around 37°C, whereas in hibernators it can approach 0°C without triggering a thermogenic response. The remarkable plasticity of the thermoregulatory system allowed mammals to thrive in variable environmental conditions and occupy a wide range of geographical habitats, but the molecular basis of thermoregulation remains poorly understood. Here we leverage the thermoregulatory differences between mice and hibernating thirteen-lined ground squirrels (Ictidomys tridecemlineatus) to investigate the mechanism of cold sensitivity in the preoptic area (POA) of the hypothalamus, a critical thermoregulatory region. We report that, in comparison to squirrels, mice have a larger proportion of cold-sensitive neurons in the POA. We further show that mouse cold-sensitive neurons express the cyclic nucleotide-gated ion channel CNGA3, and that mouse, but not squirrel, CNGA3 is potentiated by cold. Our data reveal CNGA3 as a hypothalamic cold sensor and a molecular marker to interrogate the neuronal circuitry underlying thermoregulation.
The RNA sequencing data was deposited to the Gene Expression Omnibus, accession number: GSE136396. The nucleotide and protein sequences of the cloned mouse and ground squirrel CNGA3 orthologues were deposited to GenBank under the accession numbers: MN381859 (mouse Cnga3), MN381860 (ground squirrel Cnga3).
RNAseq of cold-sensitive and cold-insensitive neurons from the preoptic area of hypothalamus of miceNCBI Gene Expression Omnibus, GSE136396.
- Viktor V Feketa
- Elena O Gracheva
- Elena O Gracheva
- Sviatoslav N Bagriantsev
- Sviatoslav N Bagriantsev
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: All animal procedures were performed in compliance with the Office of Animal Research Support of Yale University (protocols 2018-11497 and 2018-11526). Thirteen-lined ground squirrels (Ictidomys tridecemlineatus), wild-type mice (Mus musculus), and frogs (Xenopus laevis) were used for this study. Wild-type C57Bl/6J mice were purchased from Jackson Laboratory (Bar Harbor, ME). All animals were housed on a 12-h light/dark cycle (lights on at 0700) under standard laboratory conditions with ad libitum access to food and water. Both male and female mice 6-16 weeks of age weighing 17-34 g and male thirteen-lined ground squirrels 6 months-3 years of age weighing approximately 150-300 g were used for experiments. All ground squirrels were in their active (non-hibernating) state verified by daily body temperature measurements and maintained on a diet of dog food (Iams) supplemented with sunflower seeds, superworms, and fresh vegetables. Frogs were housed using standard conditions.
- Polina V Lishko, University of California, Berkeley, United States
© 2020, Feketa et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Maintaining germline genome integrity is essential and enormously complex. Although many proteins are involved in DNA replication, proofreading, and repair, mutator alleles have largely eluded detection in mammals. DNA replication and repair proteins often recognize sequence motifs or excise lesions at specific nucleotides. Thus, we might expect that the spectrum of de novo mutations – the frequencies of C>T, A>G, etc. – will differ between genomes that harbor either a mutator or wild-type allele. Previously, we used quantitative trait locus mapping to discover candidate mutator alleles in the DNA repair gene Mutyh that increased the C>A germline mutation rate in a family of inbred mice known as the BXDs (Sasani et al., 2022, Ashbrook et al., 2021). In this study we developed a new method to detect alleles associated with mutation spectrum variation and applied it to mutation data from the BXDs. We discovered an additional C>A mutator locus on chromosome 6 that overlaps Ogg1, a DNA glycosylase involved in the same base-excision repair network as Mutyh (David et al., 2007). Its effect depends on the presence of a mutator allele near Mutyh, and BXDs with mutator alleles at both loci have greater numbers of C>A mutations than those with mutator alleles at either locus alone. Our new methods for analyzing mutation spectra reveal evidence of epistasis between germline mutator alleles and may be applicable to mutation data from humans and other model organisms.
Primate evolution has led to a remarkable diversity of behavioral specializations and pronounced brain size variation among species (Barton, 2012; DeCasien and Higham, 2019; Powell et al., 2017). Gene expression provides a promising opportunity for studying the molecular basis of brain evolution, but it has been explored in very few primate species to date (e.g. Khaitovich et al., 2005; Khrameeva et al., 2020; Ma et al., 2022; Somel et al., 2009). To understand the landscape of gene expression evolution across the primate lineage, we generated and analyzed RNA-seq data from four brain regions in an unprecedented eighteen species. Here, we show a remarkable level of variation in gene expression among hominid species, including humans and chimpanzees, despite their relatively recent divergence time from other primates. We found that individual genes display a wide range of expression dynamics across evolutionary time reflective of the diverse selection pressures acting on genes within primate brain tissue. Using our samples that represent a 190-fold difference in primate brain size, we identified genes with variation in expression most correlated with brain size. Our study extensively broadens the phylogenetic context of what is known about the molecular evolution of the brain across primates and identifies novel candidate genes for the study of genetic regulation of brain evolution.