RESUMO
Temperature-dependent alternative splicing (AS) is a crucial mechanism for organisms to adapt to varying environmental temperatures. In mammals, even slight fluctuations in body temperature are sufficient to drive significant AS changes in a concerted manner. This dynamic regulation allows organisms to finely tune gene expression and protein isoform diversity in response to temperature cues, ensuring proper cellular function and physiological adaptation. Understanding the molecular mechanisms underlying temperature-dependent AS thus provides valuable insights into the intricate interplay between environmental stimuli and gene expression regulation. In this review, we provide an overview of recent advances in understanding temperature-regulated AS across various biological processes and systems. We will discuss the machinery sensing and translating temperature cues into changed AS patterns, the adaptation of the splicing regulatory machinery to extreme temperatures, the role of temperature-dependent AS in shaping the transcriptome, functional implications and the development of potential therapeutics targeting temperature-sensitive AS pathways.
Assuntos
Processamento Alternativo , Transcriptoma , Animais , Humanos , Temperatura , Regulação da Temperatura Corporal/genética , Regulação da Temperatura Corporal/fisiologia , Regulação da Expressão GênicaRESUMO
Global climate change has led to shifts in the distribution ranges of many terrestrial species, promoting their migration from lower altitudes or latitudes to higher ones. Meanwhile, successful invaders have developed genetic adaptations enabling the colonization of new environments. Over the past 40â years, Rattus tanezumi (RT) has expanded into northern China (Northwest and North China) from its southern origins. We studied the cold adaptation of RT and its potential for northward expansion by comparing it with sympatric Rattus norvegicus (RN), which is well adapted to cold regions. Through population genomic analysis, we revealed that the invading RT rats have split into three distinct populations: the North, Northwest, and Tibetan populations. The first two populations exhibited high genetic diversity, while the latter population showed remarkably low genetic diversity. These rats have developed various genetic adaptations to cold, arid, hypoxic, and high-UV conditions. Cold acclimation tests revealed divergent thermoregulation between RT and RN. Specifically, RT exhibited higher brown adipose tissue activity and metabolic rates than did RN. Transcriptome analysis highlighted changes in genes regulating triglyceride catabolic processes in RT, including Apoa1 and Apoa4, which were upregulated, under selection and associated with local adaptation. In contrast, RN showed changes in carbohydrate metabolism genes. Despite the cold adaptation of RT, we observed genotypic and phenotypic constraints that may limit its ability to cope with severe low temperatures farther north. Consequently, it is less likely that RT rats will invade and overlap with RN rats in farther northern regions.
Assuntos
Aclimatação , Temperatura Baixa , Animais , Ratos , Aclimatação/genética , China , Fenótipo , Variação Genética , Adaptação Fisiológica/genética , Regulação da Temperatura Corporal/genética , Mudança ClimáticaRESUMO
The role of the hypothalamic cold-sensitive ion channels - transient receptor potential melastatin 8 (TRPM8) and transient receptor potential ankyrin 1 (TRPA1) in homeostatic systems of thermoregulation and water-salt balance - is not clear. The interaction of homeostatic systems of thermoregulation and water-salt balance without additional temperature load did not receive due attention, too. On the models of water-balance disturbance, we tried to elucidate some aspect of these problems. Body temperature (Tbody), O2 consumption, CO2 excretion, electrical muscle activity (EMA), temperature of tail skin (Ttail), plasma osmolality, as well as gene expression of hypothalamic TRPM8 and TRPA1 have been registered in rats of 3 groups: control; water-deprived (3 days under dry-eating); and hyperhydrated (6 days without dry food, drinking liquid 4 % sucrose). No relationship was observed between plasma osmolality and gene expression of Trpm8 and Trpa1. In water-deprived rats, the constriction of skin vessels, increased fat metabolism by 10 % and increased EMA by 48 % allowed the animals to maintain Tbody unchanged. The hyperhydrated rats did not develop sufficient mechanisms, and their Tbody decreased by 0.8 °C. The development of reactions was correlated with the expression of genes of thermosensitive ion channels in the anterior hypothalamus. Ttail had a direct correlation with the expression of the Trpm8 gene, whereas EMA directly correlated with the expression of the Trpa1 gene in water-deprived group. The obtained data attract attention from the point of view of management and correction of physiological functions by modulating the ion channel gene expression.
Assuntos
Regulação da Temperatura Corporal , Canal de Cátion TRPA1 , Canais de Cátion TRPM , Animais , Ratos , Regulação da Temperatura Corporal/genética , Temperatura Baixa , Proteínas do Citoesqueleto/metabolismo , Temperatura , Canal de Cátion TRPA1/metabolismo , Canais de Cátion TRPM/metabolismoRESUMO
Local adaptation is critical in speciation and evolution, yet comprehensive studies on proximate and ultimate causes of local adaptation are generally scarce. Here, we integrated field ecological experiments, genome sequencing, and genetic verification to demonstrate both driving forces and molecular mechanisms governing local adaptation of body coloration in a lizard from the Qinghai-Tibet Plateau. We found dark lizards from the cold meadow population had lower spectrum reflectance but higher melanin contents than light counterparts from the warm dune population. Additionally, the colorations of both dark and light lizards facilitated the camouflage and thermoregulation in their respective microhabitat simultaneously. More importantly, by genome resequencing analysis, we detected a novel mutation in Tyrp1 that underpinned this color adaptation. The allele frequencies at the site of SNP 459# in the gene of Tyrp1 are 22.22% G/C and 77.78% C/C in dark lizards and 100% G/G in light lizards. Model-predicted structure and catalytic activity showed that this mutation increased structure flexibility and catalytic activity in enzyme TYRP1, and thereby facilitated the generation of eumelanin in dark lizards. The function of the mutation in Tyrp1 was further verified by more melanin contents and darker coloration detected in the zebrafish injected with the genotype of Tyrp1 from dark lizards. Therefore, our study demonstrates that a novel mutation of a major melanin-generating gene underpins skin color variation co-selected by camouflage and thermoregulation in a lizard. The resulting strong selection may reinforce adaptive genetic divergence and enable the persistence of adjacent populations with distinct body coloration.
Assuntos
Lagartos , Melaninas , Animais , Melaninas/genética , Lagartos/genética , Peixe-Zebra , Regulação da Temperatura Corporal/genética , Pigmentação da Pele/genética , CorRESUMO
The skin plays an important role in thermoregulation. Identification of genes on the skin that contribute to increased heat tolerance can be used to select animals with the best performance in warm environments. Our objective was to identify candidate genes associated with the heat stress response in the skin of Santa Ines sheep. A group of 80 sheep assessed for thermotolerance was kept in a climatic chamber for 8 days at a stress level temperature of 36 °C (10 am to 04 pm) and a maintenance temperature of 28 °C (04 pm to 10 am). Two divergent groups, with seven animals each, were formed after ranking them by thermotolerance using rectal temperature. From skin biopsy samples, total RNA was extracted, quantified, and used for RNA-seq analysis. 15,989 genes were expressed in sheep skin samples, of which 4 genes were differentially expressed (DE; FDR < 0.05) and 11 DE (FDR 0.05-0.177) between the two divergent groups. These genes are involved in cellular protection against stress (HSPA1A and HSPA6), ribosome assembly (28S, 18S, and 5S ribosomal RNA), and immune response (IGHG4, GNLY, CXCL1, CAPN14, and SAA-4). The candidate genes and main pathways related to heat tolerance in Santa Ines sheep require further investigation to understand their response to heat stress in different climatic conditions and under solar radiation. It is essential to verify whether these genes and pathways are present in different breeds and to understand the relationship between heat stress and other genes identified in this study.
Assuntos
Termotolerância , Ovinos/genética , Animais , Termotolerância/genética , Pele , Regulação da Temperatura Corporal/genética , Resposta ao Choque Térmico/genética , Perfilação da Expressão GênicaRESUMO
Heat sensation and tolerance are crucial for determining species' survival and distribution range of small mammals. As a member of the transmembrane proteins, transient receptor potential vanniloid 1 (TRPV1) is involved in the sensation and thermoregulation of heat stimuli; however, the associations between animal's heat sensitivity and TRPV1 in wild rodents are less studied. Here, we found that Mongolian gerbils (Meriones unguiculatus), a rodent species living in Mongolia grassland, showed an attenuated sensitivity to heat compared with sympatrically distributed mid-day gerbils (M. meridianus) based on a temperature preference test. To explain this phenotypical difference, we measured the TRPV1 mRNA expression of two gerbil species in the hypothalamus, brown adipose tissue, and liver, and no statistical difference was detected between two species. However, according to the bioinformatics analysis of TRPV1 gene, we identified two single amino acid mutations on two TRPV1 orthologs in these two species. Further Swiss-model analyses of two TRPV1 protein sequences indicated the disparate conformations at amino acid mutation sites. Additionally, we confirmed the haplotype diversity of TRPV1 in both species by expressing TRPV1 genes ectopicly in Escherichia coli system. Taken together, our findings supplemented genetic cues to the association between the discrepancy of heat sensitivity and the functional differentiation of TRPV1 using two wild congener gerbils, promoting the comprehension of the evolutionary mechanisms of the TRPV1 gene for heat sensitivity in small mammals.
Assuntos
Regulação da Temperatura Corporal , Temperatura Alta , Animais , Gerbillinae/metabolismo , Regulação da Temperatura Corporal/genética , Aminoácidos/metabolismo , Variação GenéticaRESUMO
An array of external factors, an important one being temperature, decide the fate of survival in a microbe. The ability of microbes to sense external cues and to regulate the expression of genes accordingly is critical for its likely survival. Among a myriad of cellular defence mechanisms, a strategy to recuperate stress involves RNA regulatory elements. RNAs own a repertoire of functions in a cell as messengers, for transfer or as a component of ribosomes. A shift from its indigenous role is as regulators of gene expression, where in the cis-encoded RNA termed as "RNA Thermometers" play a pivotal role in translational level of gene expression. In this paper, we review the occurrence, the different types and molecular mechanism of gene regulation by RNATs, with a special focus limited to the domain Bacteria. We discuss the role of RNATs in mediating expression of temperature-responsive genes like heat shock/cold attributing in heat/cold shock response and a cascade of virulence genes to evade host defence mechanisms.
Assuntos
Regulação Bacteriana da Expressão Gênica , RNA Bacteriano , Bactérias/metabolismo , Regulação da Temperatura Corporal/genética , RNA Bacteriano/genética , RNA Bacteriano/metabolismo , TermômetrosRESUMO
ISIAH (inherited stress-induced arterial hypertension) rats are characterized by high blood pressure and decreased Trpm8 gene expression in the anterior hypothalamus. Thermosensitive ion channel TRPM8 plays a critical role in the transduction of moderately cold stimuli that give rise to cool sensations. In normotensive animals, the activation of skin TRPM8 is known to induce changes in gene expression in the hypothalamus and induce alterations of thermoregulatory responses. In this work, in hypertensive rats, we studied the effects of activation of the peripheral TRPM8 by cooling and by application of a 1% menthol suspension on (1) the maintenance of body temperature balance and (2) mRNA expression of thermosensitive TRP ion channels in the hypothalamus. In these hypertensive animals, (1) pharmacological activation of peripheral TRPM8 did not affect the thermoregulatory parameters either under thermoneutral conditions or during cold exposure; (2) the expression of Trpm8 in the anterior hypothalamus approximately doubled (to the level of normotensive animals) under the influence of (a) slow cooling and (b) at pharmacological activation of the peripheral TRPM8 ion channel. The latter fact seems the quite important because it allows the proposal of a tool for correcting at least some parameters that distinguish a hypertensive state from the normotensive one.
Assuntos
Hipertensão , Canais de Cátion TRPM , Animais , Regulação da Temperatura Corporal/genética , Temperatura Baixa , Hipertensão/genética , Hipotálamo/metabolismo , Mentol/farmacologia , Ratos , Canais de Cátion TRPM/metabolismoRESUMO
The SLICK1 mutation in bovine PRLR (c.1382del; rs517047387) is a deletion mutation resulting in a protein with a truncated intracellular domain. Cattle carrying at least one allele have a phenotype characterized by a short hair coat (slick phenotype) and increased resistance to heat stress. Given the pleiotropic nature of prolactin, the mutation may affect other physiological characteristics. The liver is one organ that could potentially be affected because of the expression of PRLR. The mutation is a dominant allele, and heterozygous animals have a similar hair coat to that of animals homozygous for the mutation. Present objectives were to determine whether inheritance of the SLICK1 mutation affects liver gene expression and if animals homozygous for the SLICK1 allele differ from heterozygotes in liver gene expression and regulation of body temperature during heat stress. In one experiment, rectal and ruminal temperatures were less for Holstein heifers that were heterozygous for the SLICK1 allele compared with wildtype heifers. There were 71 differentially expressed genes in liver, with 13 upregulated and 58 downregulated in SLICK1 heterozygotes. Among the ontologies characteristic of differentially expressed genes were those related to immune function and fatty acid and amino acid metabolism. In a prospective cohort study conducted with adult Senepol cattle, body temperature and hepatic gene expression were compared between animals heterozygous or homozygous for the SLICK1 mutation. There were no differences in ruminal temperatures between genotypes, rectal temperature was higher in animals homozygous for the SLICK1 mutation, and there was only one gene in liver that was differentially expressed. It was concluded that inheritance of the SLICK1 allele can exert functional changes beyond those related to hair growth although changes in liver gene expression were not extensive. Results are also consistent with the SLICK1 allele being dominant because there were few differences in phenotype between animals inheriting one or two copies of the allele.
Assuntos
Doenças dos Bovinos , Transtornos de Estresse por Calor , Animais , Temperatura Corporal , Regulação da Temperatura Corporal/genética , Bovinos/genética , Doenças dos Bovinos/genética , Feminino , Expressão Gênica , Regulação da Expressão Gênica , Transtornos de Estresse por Calor/veterinária , Fígado , Mutação , Estudos ProspectivosRESUMO
OBJECTIVE: Uncoupling protein 1 (UCP1) is a mitochondrial protein critical for adaptive thermogenesis in adipose tissues, and it is typically believed to be restricted to thermogenic adipose tissues. UCP1-Cre transgenic mice are utilized in numerous studies to provide "brown adipose-specific" conditional gene targeting. Here, we examined the distribution of Cre and UCP1 throughout the body in UCP1-Cre reporter mice. METHODS: UCP1-Cre mice crossed to Ai14-tdTomato and Ai9-tdTomato reporter mice were used to explore the tissue distribution of Cre recombinase and Ucp1 mRNA in various tissues. UCP1-Cre mice were independently infected with either a Cre-dependent PHP.eB-tdTomato virus or a Cre-dependent AAV-tdTomato virus to determine whether and where UCP1 is actively expressed in the adult central nervous system. In situ analysis of the deposited single cell RNA sequencing data was used to evaluate Ucp1 expression in the hypothalamus. RESULTS: As expected, Ucp1 expression was detected in both brown and inguinal adipose tissues. Ucp1 expression was also detected in the kidney, adrenal glands, thymus, and hypothalamus. Consistent with detectable Ucp1 expression, tdTomato expression was also observed in brown adipose tissue, inguinal white adipose tissue, kidney, adrenal glands, and hypothalamus of both male and female UCP1-Cre; Ai14-tdTomato and UCP1-Cre; Ai9-tdTomato mice by fluorescent imaging and qPCR. Critically, expression of tdTomato, and thus UCP1, within the central nervous system was observed in regions of the brain critical for the regulation of energy homeostasis, including the ventromedial hypothalamus (VMH). CONCLUSIONS: TdTomato expression in UCP1-Cre; tdTomato mice is not restricted to thermogenic adipose tissues. TdTomato was also expressed in the kidneys, adrenal glands, and throughout the brain, including brain regions and cell types that are critical for multiple aspects of central regulation of energy homeostasis. Collectively, these data have important implications for the utility of UCP1-Cre mice as genetic tools to investigate gene function specifically in brown adipose tissue.
Assuntos
Marcação de Genes/métodos , Termogênese/fisiologia , Proteína Desacopladora 1/genética , Tecido Adiposo/metabolismo , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Regulação da Temperatura Corporal/genética , Regulação da Temperatura Corporal/fisiologia , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/fisiologia , Feminino , Hipotálamo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , RNA Mensageiro/metabolismo , Proteína Desacopladora 1/metabolismoRESUMO
In most animals, sex determination occurs at conception, when sex chromosomes are segregated following Mendelian laws. However, in multiple reptiles and fishes, this genetic sex can be overridden by external factors after fertilization or birth. In some species, the genetic sex may also be governed by multiple genes, further limiting our understanding of sex determination in such species. We used the European sea bass (Dicentrarchus labrax) as a model and combined genomic (using a single nucleotide polymorphism chip) and transcriptomic (RNA-Sequencing) approaches to thoroughly depict this polygenic sex determination system and its interaction with temperature. We estimated genetic sex tendency (eGST), defined as the estimated genetic liability to become a given sex under a liability threshold model for sex determination, which accurately predicts the future phenotypic sex. We found evidence that energetic pathways, concerning the regulation of lipids and glucose, are involved in sex determination and could explain why females tend to exhibit higher energy levels and improved growth compared to males. Besides, early exposure to high-temperature up-regulated sox3, followed by sox9a in individuals with intermediate eGST, but not in individuals showing highly female-biased eGST, providing the most parsimonious explanation for temperature-induced masculinization. This gonadal state was maintained likely by DNA methylation and the up-regulation of several genes involved in histone modifications, including jmjd1c Overall, we describe a sex determination system resulting from continuous genetic and environmental influences in an animal. Our results provide significant progress in our understanding of the mechanisms underlying temperature-induced masculinization in fish.
Assuntos
Bass/genética , Regulação da Temperatura Corporal/genética , Genótipo , Herança Multifatorial , Processos de Determinação Sexual/genética , Animais , Tamanho Corporal , Regulação da Temperatura Corporal/fisiologia , Metilação de DNA , Metabolismo Energético , Feminino , Regulação da Expressão Gênica , Gônadas/metabolismo , Histonas/genética , Histonas/metabolismo , Masculino , Reprodutibilidade dos Testes , Fatores de Transcrição SOX/genética , Fatores de Transcrição SOX/metabolismo , TemperaturaRESUMO
Deep brain temperature detection by hypothalamic warm-sensitive neurons (WSNs) has been proposed to provide feedback information relevant for thermoregulation. WSNs increase their action potential firing rates upon warming, a property that has been presumed to rely on the composition of thermosensitive ion channels within WSNs. Here, we describe a synaptic mechanism that regulates temperature sensitivity of preoptic WSNs and body temperature. Experimentally induced warming of the mouse hypothalamic preoptic area in vivo triggers body cooling. TRPM2 ion channels facilitate this homeostatic response and, at the cellular level, enhance temperature responses of WSNs, thereby linking WSN function with thermoregulation for the first time. Rather than acting within WSNs, we-unexpectedly-find TRPM2 to temperature-dependently increase synaptic drive onto WSNs by disinhibition. Our data emphasize a network-based interoceptive paradigm that likely plays a key role in encoding body temperature and that may facilitate integration of diverse inputs into thermoregulatory pathways.
Assuntos
Regulação da Temperatura Corporal/genética , Inibição Neural/genética , Neurônios/metabolismo , Área Pré-Óptica/metabolismo , Canais de Cátion TRPM/genética , Sensação Térmica/genética , Animais , Temperatura Corporal , Regulação da Temperatura Corporal/fisiologia , Interocepção/fisiologia , Camundongos , Camundongos Knockout , Área Pré-Óptica/citologia , Sinapses , Canais de Cátion TRPM/metabolismoRESUMO
Avian uncoupling protein (av-UCP) is a key protein for thermoregulation in poultry. A single nucleotide polymorphism (SNP) in the av-UCP gene has been reported in chickens. The purpose of the current study was to clarify the association between this av-UCP gene mutation and thermoregulation in chickens. Wild and mutant type chicks for the av-UCP gene SNP (g. 1270 of the av-UCP gene exon 3 with C to T substitution and amino acid substitution) were exposed to high ambient temperature. Rectal temperature, radiation temperature on the body surface, and the expression of heat dissipation behavior (wing drooping and panting) during heat exposure were measured. In addition, oxygen consumption rate in the thermoneutral zone in wild and mutant type chicks was measured. Changes in wing temperature during heat exposure in wild-type chicks were lower than those in mutants. The latency of continuous wing drooping during heat exposure in wild-type chicks was shorter than in mutant chicks. It was also found that the SNP in the av-UCP gene caused reduced oxygen consumption. These results suggest that the av-UCP gene mutation affects thermoregulation, especially heat production, in chickens.
Assuntos
Galinhas , Polimorfismo de Nucleotídeo Único , Animais , Regulação da Temperatura Corporal/genética , Galinhas/genética , Galinhas/metabolismo , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Proteínas de Desacoplamento Mitocondrial , Polimorfismo de Nucleotídeo Único/genética , Proteína Desacopladora 1/genéticaRESUMO
Transient receptor potential vanilloid 4 (TRPV4) is an osmosensory cation channel that respond to an increase in cell volume and participates in various physiological functions. Among organisms in aquatic environments, euryhaline teleost is are suitable experimental models to study ion channel proteins related to physiological functions involving osmosensing. Among the studies of various regulatory molecules that mediate osmotic regulation in fish, however, information is lacking, particularly on the TRP family. This study investigated the structural characteristics of theTRPV4 gene of chum salmon (Oncorhynchus keta) and their responses to changes in salinity and temperature. Interestingly, TRPV4 generates transcript variants of the intron-retention form through alternative splicing, resulting in a frameshift leading to the generation of transcripts of different structures. In particular, TRPV4 x1 and TRPV x2 mRNAs were predominant in the gill and skin including at the lateral line. The expression levels of chum salmon TRPV4 x1 were significantly increased with increase in salinity and temperature, whereas TRPV4 x2 mainly responded to temperature decrease. Overall, these results demonstrate for the first time the effects of salinity and temperature on the expression of two salmonid TRPV4 transcript variants, suggesting their contribution to the regulation of hydromineral balance.
Assuntos
Regulação da Temperatura Corporal/genética , Oncorhynchus keta/genética , Oncorhynchus keta/fisiologia , Osmorregulação/genética , RNA Mensageiro/genética , Canais de Cátion TRPV/genética , Animais , Líquidos Corporais/fisiologia , Variação Genética , Filogenia , Salinidade , Canais de Cátion TRPV/classificação , Temperatura , Transcrição GênicaRESUMO
The preoptic area (POA) is a key brain region for regulation of body temperature (Tb), dictating thermogenic, cardiovascular, and behavioral responses that control Tb. Previously characterized POA neuronal populations all reduced Tb when activated. Using mice, we now identify POA neurons expressing bombesin-like receptor 3 (POABRS3) as a population whose activation increased Tb; inversely, acute inhibition of these neurons reduced Tb. POABRS3 neurons that project to either the paraventricular nucleus of the hypothalamus or the dorsomedial hypothalamus increased Tb, heart rate, and blood pressure via the sympathetic nervous system. Long-term inactivation of POABRS3 neurons caused increased Tb variability, overshooting both increases and decreases in Tb set point, with RNA expression profiles suggesting multiple types of POABRS3 neurons. Thus, POABRS3 neuronal populations regulate Tb and heart rate, contribute to cold defense, and fine-tune feedback control of Tb. These findings advance understanding of homeothermy, a defining feature of mammalian biology.
Assuntos
Regulação da Temperatura Corporal , Frequência Cardíaca , Neurônios/fisiologia , Área Pré-Óptica/metabolismo , Receptores da Bombesina/metabolismo , Animais , Temperatura Corporal/genética , Regulação da Temperatura Corporal/genética , Frequência Cardíaca/genética , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/citologia , Neurônios/metabolismo , Área Pré-Óptica/citologia , Receptores da Bombesina/genética , Transdução de Sinais/genética , Sistema Nervoso Simpático/fisiologia , Termogênese/genéticaRESUMO
Febrile seizures (FSs) are the most common convulsion in infancy and childhood. Considering the limitations of current treatments, it is important to examine the mechanistic cause of FSs. Prompted by a genome-wide association study identifying TMEM16C (also known as ANO3) as a risk factor of FSs, we showed previously that loss of TMEM16C function causes hippocampal neuronal hyperexcitability [Feenstra et al., Nat. Genet. 46, 1274-1282 (2014)]. Our previous study further revealed a reduction in the number of warm-sensitive neurons that increase their action potential firing rate with rising temperature of the brain region harboring these hypothalamic neurons. Whereas central neuronal hyperexcitability has been implicated in FSs, it is unclear whether the maximal temperature reached during fever or the rate of body temperature rise affects FSs. Here we report that mutant rodent pups with TMEM16C eliminated from all or a subset of their central neurons serve as FS models with deficient thermoregulation. Tmem16c knockout (KO) rat pups at postnatal day 10 (P10) are more susceptible to hyperthermia-induced seizures. Moreover, they display a more rapid rise of body temperature upon heat exposure. In addition, conditional knockout (cKO) mouse pups (P11) with TMEM16C deletion from the brain display greater susceptibility of hyperthermia-induced seizures as well as deficiency in thermoregulation. We also found similar phenotypes in P11 cKO mouse pups with TMEM16C deletion from Ptgds-expressing cells, including temperature-sensitive neurons in the preoptic area (POA) of the anterior hypothalamus, the brain region that controls body temperature. These findings suggest that homeostatic thermoregulation plays an important role in FSs.
Assuntos
Regulação da Temperatura Corporal/genética , Canais de Cloreto/genética , Febre/genética , Hipertermia/genética , Área Pré-Óptica/metabolismo , Convulsões Febris/genética , Potenciais de Ação/fisiologia , Animais , Animais Recém-Nascidos , Temperatura Corporal/efeitos dos fármacos , Temperatura Corporal/fisiologia , Canais de Cloreto/deficiência , Feminino , Febre/induzido quimicamente , Febre/metabolismo , Febre/fisiopatologia , Expressão Gênica , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Hipertermia/metabolismo , Hipertermia/fisiopatologia , Ácido Caínico/administração & dosagem , Masculino , Camundongos , Camundongos Knockout , Neurônios/metabolismo , Neurônios/patologia , Área Pré-Óptica/fisiopatologia , Isoformas de Proteínas/deficiência , Isoformas de Proteínas/genética , Ratos , Convulsões Febris/induzido quimicamente , Convulsões Febris/metabolismo , Convulsões Febris/fisiopatologiaRESUMO
Adrenergic stimulation of brown adipocytes alters mitochondrial dynamics, including the mitochondrial fusion protein optic atrophy 1 (OPA1). However, direct mechanisms linking OPA1 to brown adipose tissue (BAT) physiology are incompletely understood. We utilized a mouse model of selective OPA1 deletion in BAT (OPA1 BAT KO) to investigate the role of OPA1 in thermogenesis. OPA1 is required for cold-induced activation of thermogenic genes in BAT. Unexpectedly, OPA1 deficiency induced fibroblast growth factor 21 (FGF21) as a BATokine in an activating transcription factor 4 (ATF4)-dependent manner. BAT-derived FGF21 mediates an adaptive response by inducing browning of white adipose tissue, increasing resting metabolic rates, and improving thermoregulation. However, mechanisms independent of FGF21, but dependent on ATF4 induction, promote resistance to diet-induced obesity in OPA1 BAT KO mice. These findings uncover a homeostatic mechanism of BAT-mediated metabolic protection governed in part by an ATF4-FGF21 axis, which is activated independently of BAT thermogenic function.
Assuntos
Tecido Adiposo Marrom/metabolismo , Regulação da Temperatura Corporal/genética , Fatores de Crescimento de Fibroblastos/metabolismo , GTP Fosfo-Hidrolases/genética , Deleção de Genes , Adipócitos Marrons/fisiologia , Tecido Adiposo Branco/fisiologia , Animais , Feminino , Fatores de Crescimento de Fibroblastos/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/genéticaRESUMO
Humans sweat to cool their bodies and have by far the highest eccrine sweat gland density among primates. Humans' high eccrine gland density has long been recognized as a hallmark human evolutionary adaptation, but its genetic basis has been unknown. In humans, expression of the Engrailed 1 (EN1) transcription factor correlates with the onset of eccrine gland formation. In mice, regulation of ectodermal En1 expression is a major determinant of natural variation in eccrine gland density between strains, and increased En1 expression promotes the specification of more eccrine glands. Here, we show that regulation of EN1 has evolved specifically on the human lineage to promote eccrine gland formation. Using comparative genomics and validation of ectodermal enhancer activity in mice, we identified a human EN1 skin enhancer, hECE18. We showed that multiple epistatically interacting derived substitutions in the human ECE18 enhancer increased its activity compared with nonhuman ape orthologs in cultured keratinocytes. Repression of hECE18 in human cultured keratinocytes specifically attenuated EN1 expression, indicating this element positively regulates EN1 in this context. In a humanized enhancer knock-in mouse, hECE18 increased developmental En1 expression in the skin to induce the formation of more eccrine glands. Our study uncovers a genetic basis contributing to the evolution of one of the most singular human adaptations and implicates multiple interacting mutations in a single enhancer as a mechanism for human evolutionary change.
Assuntos
Regulação da Temperatura Corporal/genética , Regulação da Temperatura Corporal/fisiologia , Proteínas de Homeodomínio/genética , Animais , Evolução Biológica , Glândulas Écrinas/metabolismo , Glândulas Écrinas/fisiologia , Ectoderma , Elementos Facilitadores Genéticos/genética , Evolução Molecular , Proteínas de Homeodomínio/metabolismo , Humanos , Queratinócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação , Sequências Reguladoras de Ácido Nucleico/genética , Pele/metabolismo , Sudorese/genética , Sudorese/fisiologia , Fatores de Transcrição/genéticaRESUMO
Whether cyclooxygenase (COX)/prostaglandin E2 (PGE2) thermoregulatory pathways, observed in rodents, present in humans? Participants (n = 9) were exposed to three environments; cold (20 °C), thermoneutral (30 °C) and hot (40 °C) for 120 min. Core (Tc)/skin temperature and thermal perception were recorded every 15 min, with COX/PGE2 concentrations determined at baseline, 60 and 120 min. Linear mixed models identified differences between and within subjects/conditions. Random coefficient models determined relationships between Tc and COX/PGE2. Tc [mean (range)] increased in hot [+ 0.8 (0.4-1.2) °C; p < 0.0001; effect size (ES): 2.9], decreased in cold [- 0.5 (- 0.8 to - 0.2) °C; p < 0.0001; ES 2.6] and was unchanged in thermoneutral [+ 0.1 (- 0.2 to 0.4) °C; p = 0.3502]. A relationship between COX2/PGE2 in cold (p = 0.0012) and cold/thermoneutral [collapsed, condition and time (p = 0.0243)] was seen, with higher PGE2 associated with higher Tc. A within condition relationship between Tc/PGE2 was observed in thermoneutral (p = 0.0202) and cold/thermoneutral [collapsed, condition and time (p = 0.0079)] but not cold (p = 0.0631). The data suggests a thermogenic response of the COX/PGE2 pathway insufficient to defend Tc in cold. Further human in vivo research which manipulates COX/PGE2 bioavailability and participant acclimation/acclimatization are warranted to elucidate the influence of COX/PGE2 on Tc.
Assuntos
Regulação da Temperatura Corporal/genética , Ciclo-Oxigenase 2/genética , Dinoprostona/genética , Temperatura Cutânea/genética , Adulto , Disponibilidade Biológica , Temperatura Corporal , Temperatura Baixa , Temperatura Alta , Humanos , MasculinoRESUMO
The hair follicle (HF) is a highly conserved sensory organ associated with the immune response against pathogens, thermoregulation, sebum production, angiogenesis, neurogenesis and wound healing. Although recent advances in lineage-tracing techniques and the ability to profile gene expression in small populations of cells have increased the understanding of how stem cells operate during hair growth and regeneration, the construction of functional follicles with cycling activity is still a great challenge for the hair research field and for translational and clinical applications. Given that hair formation and cycling rely on tightly coordinated epithelial-mesenchymal interactions, we thus review potential cell sources with HF-inducive capacities and summarize current bioengineering strategies for HF regeneration with functional restoration.