Abstract Challenging environmental conditions can drive the evolution of extreme physiological traits. The naked mole-rat has evolved to survive and thrive in a low oxygen, high carbon dioxide environment that would be deadly to humans and most other mammals. The naked mole-rat’s lifestyle is unusual in that this species combines subterranean living and living in large, social groups of up to 300 + individuals. Many respiring animals in a closed environment can lead to depletion of oxygen (hypoxia) and accumulation of carbon dioxide (hypercapnia). Naked mole-rats display a variety of physiological traits that negate the adverse effects of living in this atmosphere. For hypoxia tolerance, naked mole-rats have a low resting metabolism, high affinity hemoglobin, intrinsic brain tolerance, the ability to use fructose for anaerobic glycolysis, and the ability to enter a low energy, suspended animation-like state. For hypercapnia tolerance, these animals have a mutation in a voltage gated sodium channel that effectively eliminates neuronal responses to tissue acidosis. In other mammals, acidosis from exposure to high concentrations of carbon dioxide induces pain and pulmonary edema. Understanding these mechanisms of extreme physiology is not only inherently interesting, but it may lead to biomedical breakthroughs in research on heart attacks, strokes, and pain pathologies.
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Naked Mole-Rats Demonstrate Profound Tolerance to Low Oxygen, High Carbon Dioxide, and Chemical Pain
Naked mole-rats (Heterocephalus glaber) are very unusual among subterranean mammals in that they live in large colonies and are extremely social, spending large amounts of time gathered together in underground nests more than a meter below the surface. Many respiring individuals resting in deep, poorly ventilated nests deplete the oxygen supply and increase the concentration of carbon dioxide. Consistent with living in that atmosphere, naked mole-rats tolerate levels of low oxygen and high carbon dioxide that are deadly to most surface-dwelling mammals. Naked mole-rats appear to have evolved a number of remarkable adaptations to be able to thrive in this harsh atmosphere. In order to successfully survive low oxygen atmospheres, they conserve energy utilization by reducing the physiological activity of all organs, manifest by reduced heart rate and brain activity. Amazingly, they resort to the anaerobic metabolism of fructose rather than glucose as a fuel to generate energy when challenged by anoxia. Similarly, high carbon dioxide atmospheres normally cause tissue acidosis, while naked mole-rats have a genetic mutation preventing both acid-induced pain and pulmonary edema. Together, these putative adaptations and the tolerances they provide make the naked mole-rat an important model for studying a host of biomedical challenges.
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- Award ID(s):
- 2201647
- NSF-PAR ID:
- 10432428
- Date Published:
- Journal Name:
- Animals
- Volume:
- 13
- Issue:
- 5
- ISSN:
- 2076-2615
- Page Range / eLocation ID:
- 819
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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ABSTRACT Around the world and across taxa, subterranean mammals show remarkable convergent evolution in morphology (e.g., reduced external ears, small eyes, shortened limbs and tails). This is true of sensory systems as well (e.g., loss of object vision and high frequency hearing). The naked mole‐rat (
Heterocephalus glaber -
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Changes in gene regulation are thought to underlie most phenotypic differences between species. For subterranean rodents such as the naked mole-rat, proposed phenotypic adaptations include hypoxia tolerance, metabolic changes, and cancer resistance. However, it is largely unknown what regulatory changes may associate with these phenotypic traits, and whether these are unique to the naked mole-rat, the mole-rat clade, or are also present in other mammals. Here, we investigate regulatory evolution in the heart and liver from two African mole-rat species and two rodent outgroups using genome-wide epigenomic profiling. First, we adapted and applied a phylogenetic modeling approach to quantitatively compare epigenomic signals at orthologous regulatory elements and identified thousands of promoter and enhancer regions with differential epigenomic activity in mole-rats. These elements associate with known mole-rat adaptations in metabolic and functional pathways and suggest candidate genetic loci that may underlie mole-rat innovations. Second, we evaluated ancestral and species-specific regulatory changes in the study phylogeny and report several candidate pathways experiencing stepwise remodeling during the evolution of mole-rats, such as the insulin and hypoxia response pathways. Third, we report nonorthologous regulatory elements overlap with lineage-specific repetitive elements and appear to modify metabolic pathways by rewiring of HNF4 and RAR/RXR transcription factor binding sites in mole-rats. These comparative analyses reveal how mole-rat regulatory evolution informs previously reported phenotypic adaptations. Moreover, the phylogenetic modeling framework we propose here improves upon the state of the art by addressing known limitations of inter-species comparisons of epigenomic profiles and has broad implications in the field of comparative functional genomics.
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Abstract Compared to many other rodent species, naked mole rats (
Heterocephalus glaber ) have elevated auditory thresholds, poor frequency selectivity, and limited ability to localize sound. Because the cochlea is responsible for encoding and relaying auditory signals to the brain, we used immunofluorescence and quantitative image analysis to examine cochlear innervation in mature and developing naked mole rats compared to mice (Mus musculus ), gerbils (Meriones unguiculatus ), and Damaraland mole rats (Fukomys damarensis ), another subterranean rodent. In comparison to mice and gerbils, we observed alterations in afferent and efferent innervation as well as their patterns of developmental refinement in naked and Damaraland mole rats. These alterations were, however, not always shared similarly between naked and Damaraland mole rats. Most conspicuously, in both naked and Damaraland mole rats, inner hair cell (IHC) afferent ribbon density was reduced, whereas outer hair cell afferent ribbon density was increased. Naked and Damaraland mole rats also showed reduced lateral and medial efferent terminal density. Developmentally, naked mole rats showed reduced and prolonged postnatal reorganization of afferent and efferent innervation. Damaraland mole rats showed no evidence of postnatal reorganization. Differences in cochlear innervation specifically between the two subterranean rodents and more broadly among rodents provides insight into the cochlear mechanisms that enhance frequency sensitivity and sound localization, maturation of the auditory system, and the evolutionary adaptations occurring in response to subterranean environments. -
Life underground often leads to animals having specialized auditory systems to accommodate the constraints of acoustic transmission in tunnels. Despite living underground, naked mole-rats use a highly vocal communication system, implying that they rely on central auditory processing. However, little is known about these animals' central auditory system, and whether it follows a similar developmental time course as other rodents. Naked mole-rats show slowed development in the hippocampus suggesting they have altered brain development compared to other rodents. Here, we measured morphological characteristics and voltage-gated potassium channel K v 3.3 expression and protein levels at different key developmental time points (postnatal days 9, 14, 21 and adulthood) to determine whether the auditory brainstem (lateral superior olive and medial nucleus of the trapezoid body) develops similarly to two common auditory rodent model species: gerbils and mice. Additionally, we measured the hearing onset of naked mole-rats using auditory brainstem response recordings at the same developmental timepoints. In contrast with other work in naked mole-rats showing that they are highly divergent in many aspects of their physiology, we show that naked mole-rats have a similar hearing onset, between postnatal day (P) 9 and P14, to many other rodents. On the other hand, we show some developmental differences, such as a unique morphology and K v 3.3 protein levels in the brainstem.more » « less
- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.3390/ani13050819
