Developing sex-accurate cell culture environments
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Sensory input, sex and function shape hypothalamic cell type development
Mammalian behaviour and physiology undergo major changes in early life. Young animals rely on conspecifics to meet their needs and start showing nutritional independence and sex-specific social interactions at weaning and puberty, respectively. How neuronal populations regulating homeostatic functions and social behaviours develop during these transitions remains unclear. We used paired transcriptomic and chromatin accessibility profiling to examine the developmental trajectories of neuronal populations in the hypothalamic preoptic region, where cell types with key roles in physiological and behavioural control have been identified1,2,3,4,5,6. These data show a marked diversity of developmental trajectories shaped by the sex of the animal, and the location and behavioural or physiological function of the corresponding cell types. We identify key stages of preoptic development, including early diversification, perinatal emergence of sex differences, postnatal maturation and refinement of signalling networks, and nonlinear transcriptional changes accelerating at the time of weaning and puberty. We assessed preoptic development in various sensory mutants and find a major role for vomeronasal sensing in the timing of preoptic cell type maturation. These results provide new insights into the development of neurons controlling homeostatic functions and social behaviours and lay ground for examining the dynamics of these functions in early life.
Accelerated differentiation of neo-W nuclear-encoded mitochondrial genes between two climate-associated bird lineages signals potential co-evolution with mitogenomes
There is considerable evidence for mitochondrial-nuclear co-adaptation as a key evolutionary driver. Hypotheses regarding the roles of sex-linkage have emphasized Z-linked nuclear genes with mitochondrial function (N-mt genes), whereas it remains contentious whether the perfect co-inheritance of W genes with mitogenomes could hinder or facilitate co-adaptation. Young (neo-) sex chromosomes that possess relatively many N-mt genes compared to older chromosomes provide unprecedented hypothesis-testing opportunities. Eastern Yellow Robin (EYR) lineages in coastal and inland habitats with different climates are diverged in mitogenomes, and in a ~ 15.4 Mb nuclear region enriched with N-mt genes, in contrast with otherwise-similar nuclear genomes. This nuclear region maps to passerine chromosome 1A, previously found to be neo-sex in the inland EYR genome. To compare sex-linked Chr1A-derived genes between lineages, we assembled and annotated the coastal EYR genome. We found that: (i) the coastal lineage shares a similar neo-sex system with the inland lineage, (ii) neo-W and neo-Z N-mt genes are not more diverged between lineages than are comparable non-N-mt genes, and showed little evidence for broad positive selection, (iii) however, W-linked N-mt genes are more diverged between lineages than are their Z-linked gametologs. The latter effect was ~7 times stronger for N-mt than non-N-mt genes, suggesting that W-linked N-mt genes might have diverged between lineages under environmental selection through co-evolution with mitogenomes. Finally, we identify a candidate gene driver for divergent selection, NDUFA12. Our data represent a rare example suggesting a possible role for W-associated mitochondrial-nuclear interactions in climate-associated adaptation and lineage differentiation.
Nitrogen transfer and cross-feeding between Azotobacter chroococcum and Paracoccus aminovorans promotes pyrene degradation
Nitrogen is a limiting nutrient for degraders function in hydrocarbon-contaminated environments. Biological nitrogen fixation by diazotrophs is a natural solution for supplying bioavailable nitrogen. Here, we determined whether the diazotroph Azotobacter chroococcum HN can provide nitrogen to the polycyclic aromatic hydrocarbon-degrading bacterium Paracoccus aminovorans HPD-2 and further explored the synergistic interactions that facilitate pyrene degradation in nitrogen-deprived environments. We found that A. chroococcum HN and P. aminovorans HPD-2 grew and degraded pyrene more quickly in co-culture than in monoculture. Surface-enhanced Raman spectroscopy combined with 15N stable isotope probing (SERS − 15N SIP) demonstrated that A. chroococcum HN provided nitrogen to P. aminovorans HPD-2. Metabolite analysis and feeding experiments confirmed that cross-feeding occurred between A. chroococcum HN and P. aminovorans HPD-2 during pyrene degradation. Transcriptomic and metabolomic analyses further revealed that co-culture significantly upregulated key pathways such as nitrogen fixation, aromatic compound degradation, protein export, and the TCA cycle in A. chroococcum HN and quorum sensing, aromatic compound degradation and ABC transporters in P. aminovorans HPD-2. Phenotypic and fluorescence in situ hybridization (FISH) assays demonstrated that A. chroococcum HN produced large amounts of biofilm and was located at the bottom of the biofilm in co-culture, whereas P. aminovorans HPD-2 attached to the surface layer and formed a bridge-like structure with A. chroococcum HN. This study demonstrates that distinct syntrophic interactions occur between A. chroococcum HN and P. aminovorans HPD-2 and provides support for their combined use in organic pollutant degradation in nitrogen-deprived environments.
Sex-specific and cell-type-specific changes in chaperone-mediated autophagy across tissues during aging
Aging leads to progressive decline in organ and tissue integrity and function, partly due to loss of proteostasis and autophagy malfunctioning. A decrease with age in chaperone-mediated autophagy (CMA), a selective type of lysosomal degradation, has been reported in various organs and cells from rodents and humans. Disruption of CMA recapitulates features of aging, whereas activating CMA in mice protects against age-related diseases such as Alzheimer’s, retinal degeneration and/or atherosclerosis. However, sex-specific and cell-type-specific differences in CMA with aging remain unexplored. Here, using CMA reporter mice and single-cell transcriptomic data, we report that most organs and cell types show CMA decline with age, with males exhibiting a greater decline with aging. Reduced CMA is often associated with fewer lysosomes competent for CMA. Transcriptional downregulation of CMA genes may further contribute to CMA decline, especially in males. These findings suggest that CMA differences may influence organ vulnerability to age-related degeneration.
Polygenic scores for autism are associated with reduced neurite density in adults and children from the general population
Genetic variants linked to autism are thought to change cognition and behaviour by altering the structure and function of the brain. Although a substantial body of literature has identified structural brain differences in autism, it is unknown whether autism-associated common genetic variants are linked to changes in cortical macro- and micro-structure. We investigated this using neuroimaging and genetic data from adults (UK Biobank, N = 31,748) and children (ABCD, N = 4928). Using polygenic scores and genetic correlations we observe a robust negative association between common variants for autism and a magnetic resonance imaging derived phenotype for neurite density (intracellular volume fraction) in the general population. This result is consistent across both children and adults, in both the cortex and in white matter tracts, and confirmed using polygenic scores and genetic correlations. There were no sex differences in this association. Mendelian randomisation analyses provide no evidence for a causal relationship between autism and intracellular volume fraction, although this should be revisited using better powered instruments. Overall, this study provides evidence for shared common variant genetics between autism and cortical neurite density.
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