Soma-to-Germline miRNA inheritance via Yolk Promotes Stress Resilience in Progeny [mRNA]
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ABSTRACT: At the onset of reproduction, oviparous animals synthesize large amounts of yolk in somatic tissues to provide lipids and other nutrients to their progeny. However, whether the yolk transports other types of molecules, such as RNAs with gene regulatory functions, remains largely unexplored. Here, we have biochemically purified the yolk in the nematode Caenorhabditis elegans and show it contains microRNAs (miRNAs). We provide evidence that the yolk transports such miRNAs from the mother’s intestine to the embryos via the lipoprotein yolk receptor RME-2. These yolk-enriched miRNAs inherited by the embryos regulate the transcriptomes of developing larvae. Moreover, environmental stresses and maternal age modulate the transfer of yolk-enriched miRNAs, providing stress resilience benefits to progeny. This discovery establishes a novel paradigm in intergenerational gene regulation, where the gut-germline axis orchestrates the transmission of environmental cues through yolk-enriched miRNAs. Our work reveals a new mechanism underlying the soma-to-germline transfer of epigenetic information in animals.
Project description:At the onset of reproduction, oviparous animals synthesize large amounts of yolk in somatic tissues to provide lipids and other nutrients to their progeny. However, whether the yolk transports other types of molecules, such as RNAs with gene regulatory functions, remains largely unexplored. Here, we have biochemically purified the yolk in the nematode Caenorhabditis elegans and show it contains microRNAs (miRNAs). We provide evidence that the yolk transports such miRNAs from the mother’s intestine to the embryos via the lipoprotein yolk receptor RME-2. These yolk-enriched miRNAs inherited by the embryos regulate the transcriptomes of developing larvae. Moreover, environmental stresses and maternal age modulate the transfer of yolk-enriched miRNAs, providing stress resilience benefits to progeny. This discovery establishes a novel paradigm in intergenerational gene regulation, where the gut-germline axis orchestrates the transmission of environmental cues through yolk-enriched miRNAs. Our work reveals a new mechanism underlying the soma-to-germline transfer of epigenetic information in animals.
Project description:Oviparous animals support reproduction via the incorporation of yolk as a nutrient source into the eggs. In Caenorhabditis elegans, however, yolk proteins seem dispensable for fecundity, despite constituting the vast majority of the embryonic protein pool and acting as carriers for nutrient-rich lipids. Here, we used yolk protein-deprived C. elegans mutants to gain insight into the traits that may yet be influenced by yolk rationing. We show that massive yolk provisioning confers a temporal advantage during embryogenesis, while also increasing early juvenile body size and promoting competitive fitness. Opposite to species that reduce egg production under yolk deprivation, our results indicate that C. elegans relies on yolk as a fail-safe to secure offspring survival, rather than to maintain offspring numbers.
Project description:Microglia aid in refining central gustatory circuits during normal development. This process is arrested by merely restricting their mother’s dietary sodium during a limited, early prenatal period when microglia progenitors migrate from the yolk-sac to the brain.
Project description:In animals, maternal diet and environment can influence the health of offspring. Whether and how maternal dietary choice impacts the nervous system across multiple generations is not well understood. Here, we show that feeding Caenorhabditis elegans with ursolic acid (UA), a natural plant product, reduces adult-onset neurodegeneration intergenerationally. UA provides neuroprotection by enhancing maternal provisioning of sphingosine-1-phosphate (S1P) - a bioactive sphingolipid. Intestine-to-oocyte S1P transfer is required for intergenerational neuroprotection and is dependent on the RME-2 lipoprotein yolk receptor. S1P acts intergenerationally by upregulating transcription of the acid ceramidase-1 (asah-1) gene in the intestine. Spatially regulating sphingolipid metabolism is critical as inappropriate asah-1 expression in neurons causes developmental axon outgrowth defects. Our results show that sphingolipid homeostasis impacts the development and intergenerational health of the nervous system. The ability of specific lipid metabolites to act as messengers between generations may have broad implications for dietary choice during reproduction.
Project description:Inherited mitochondrial DNA (mtDNA) diseases transmit maternally and cause severe phenotypes. Since no effective treatment or genetic screening is available, nuclear genome transfer between patients’ and healthy eggs to replace mutant mtDNAs holds promises. Since polar body contains very few mitochondria and share same genomic material as oocyte, here we perform polar body transfer to prevent the transmission of inherited mtDNA variants. We compare the value of different germline genome transfer (spindle-chromosome, pronuclear, first and second polar body) in a mouse model. Reconstructed embryos support normal fertilization and produce live offspring. Strikingly, genetic analysis confirms F1 generation after polar body transfer possesses minimal donor mtDNA carry-over compared with spindle-chromosome (low/medium carry-over) and pronuclear (medium/high carry-over) transfer. Moreover, mtDNA genotype remains stable in F2 generation of progeny after polar body transfer. Our preclinical model demonstrates polar body transfer holds great potential in preventing the transmission of inherited mtDNA diseases. The objective of the present study was to detect genomic aberrations between PB1 and its counterpart, spindle-chromosome complex in human MII oocyte, PB2 and female pronucleus in human zygote at a single-cell level.
Project description:Inherited mitochondrial DNA (mtDNA) diseases transmit maternally and cause severe phenotypes. Since no effective treatment or genetic screening is available, nuclear genome transfer between patients’ and healthy eggs to replace mutant mtDNAs holds promises. Since polar body contains very few mitochondria and share same genomic material as oocyte, here we perform polar body transfer to prevent the transmission of inherited mtDNA variants. We compare the value of different germline genome transfer (spindle-chromosome, pronuclear, first and second polar body) in a mouse model. Reconstructed embryos support normal fertilization and produce live offspring. Strikingly, genetic analysis confirms F1 generation after polar body transfer possesses minimal donor mtDNA carry-over compared with spindle-chromosome (low/medium carry-over) and pronuclear (medium/high carry-over) transfer. Moreover, mtDNA genotype remains stable in F2 generation of progeny after polar body transfer. Our preclinical model demonstrates polar body transfer holds great potential in preventing the transmission of inherited mtDNA diseases.
Project description:The differences of reproductive processes at molecular levels between the viviparous and oviparous animals are still unclear, and in the oviparous animal, the locations to synthetize sex hormones and also the trends to enrich sex hormones during follicle development are different from that of viviparous animals. To explore the commonalities (key factors for follicular development) and individualities (factors that cause differences among species) in the follicular development of viviparous and oviparous animals, we compared the similarities and differences in follicle development between viviparous and oviparous animals in terms of transcriptome and super-enhancer-based transcriptional regulation, using humans, bovines, and mice as representatives of viviparous animals and chickens, for oviparous animals. It was found that follicle development in molecular terms tended to be more conservative between viviparous and oviparous animals. Estrogen receptors and androgen receptors occupied central positions in the transcriptional regulatory networks of viviparous and oviparous animals respectively, which may be related with differences in the synthesis and secretion of sex hormones between oviparous and viviparous animals. The role of androgen receptors in chicken follicle development was verified through cell level and field experiments. Our study would facilitate to extend existing results of follicle development in viviparous animals to oviparous animals, and our results emphasized the importance of the androgen receptor in chicken follicle development. Comparative analysis among different species in follicle development will help us to gain insight on the mechanisms of follicle development.
Project description:The differences of reproductive processes at molecular levels between the viviparous and oviparous animals are still unclear, and in the oviparous animal, the locations to synthetize sex hormones and also the trends to enrich sex hormones during follicle development are different from that of viviparous animals. To explore the commonalities (key factors for follicular development) and individualities (factors that cause differences among species) in the follicular development of viviparous and oviparous animals, we compared the similarities and differences in follicle development between viviparous and oviparous animals in terms of transcriptome and super-enhancer-based transcriptional regulation, using humans, bovines, and mice as representatives of viviparous animals and chickens, for oviparous animals. It was found that follicle development in molecular terms tended to be more conservative between viviparous and oviparous animals. Estrogen receptors and androgen receptors occupied central positions in the transcriptional regulatory networks of viviparous and oviparous animals respectively, which may be related with differences in the synthesis and secretion of sex hormones between oviparous and viviparous animals. The role of androgen receptors in chicken follicle development was verified through cell level and field experiments. Our study would facilitate to extend existing results of follicle development in viviparous animals to oviparous animals, and our results emphasized the importance of the androgen receptor in chicken follicle development. Comparative analysis among different species in follicle development will help us to gain insight on the mechanisms of follicle development.