Particulate matter leaves a bitter taste in testes
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Disrupting Amh and androgen signaling reveals their distinct roles in zebrafish gonadal differentiation and gametogenesis
Sex determination and differentiation in zebrafish involve a complex interaction of male and female-promoting factors. While Dmrt1 has been established as a critical male-promoting factor, the roles of Anti-Müllerian hormone (Amh) and androgen signaling remain less clear. This study employed an estrogen-deficient zebrafish model (cyp19a1a-/-) to dissect individual and combined roles of Amh and androgen receptor (Ar) signaling in gonadal differentiation and gametogenesis. Loss of amh, but not ar, could rescue all-male phenotype of cyp19a1a-/-, leading to female or intersex, confirming the role of Amh in promoting male differentiation. This rescue was recapitulated in bmpr2a-/- but not bmpr2b-/-, supporting Bmpr2a as the type II receptor for Amh in zebrafish. Interestingly, while disruption of amh or ar had delayed spermatogenesis, the double mutant (amh-/-;ar-/-) exhibited severely impaired spermatogenesis, highlighting their compensatory roles. While Amh deficiency led to testis hypertrophy, likely involving a compensatory increase in Ar signaling, Ar deficiency resulted in reduced hypertrophy in double mutant males. Furthermore, phenotype analysis of triple mutant (amh-/-;ar-/-;cyp19a1a-/-) provided evidence that Ar participated in early follicle development. This study provides novel insights into complex interplay between Amh and androgen signaling in zebrafish sex differentiation and gametogenesis, highlighting their distinct but cooperative roles in male development.
Genome-wide analysis identifies novel shared loci between depression and white matter microstructure
Depression, a complex and heritable psychiatric disorder, is associated with alterations in white matter microstructure, yet their shared genetic basis remains largely unclear. Utilizing the largest available genome-wide association study (GWAS) datasets for depression (N = 674,452) and white matter microstructure (N = 33,224), assessed through diffusion tensor imaging metrics such as fractional anisotropy (FA) and mean diffusivity (MD), we employed linkage disequilibrium score regression method to estimate global genetic correlations, local analysis of [co]variant association approach to pinpoint genomic regions with local genetic correlations, and conjunctional false discovery rate analysis to identify shared variants. Our findings revealed that depression showed significant local genetic correlations with FA in 37 genomic regions and with MD in 59 regions, while global genetic correlations were weak. Variant-level analysis identified 78 distinct loci jointly associated with depression (25 novel loci) and FA (35 novel loci), and 41 distinct loci associated with depression (17 novel loci) and MD (25 novel loci). Further analyses showed that these shared loci exhibited both concordant and discordant effect directions between depression and white matter traits, as well as distinct yet overlapping hemispheric patterns in their genetic architecture. Enrichment analysis of these shared loci implicated biological processes related to metabolism and regulation. This study provides evidence of a mixed-direction shared genetic architecture between depression and white matter microstructure. The identification of specific loci and pathways offers potential insights for developing targeted interventions to improve white matter integrity and alleviate depressive symptoms.
Co-option and neofunctionalization of stomatal executors for defence against herbivores in Brassicales
Co-option of gene regulatory networks leads to the acquisition of new cell types and tissues. Stomata, valves formed by guard cells (GCs), are present in most land plants and regulate CO2 exchange. The transcription factor (TF) FAMA globally regulates GC differentiation. In the Brassicales, FAMA also promotes the development of idioblast myrosin cells (MCs), another type of specialized cell along the vasculature essential for Brassicales-specific chemical defences. Here we show that in Arabidopsis thaliana, FAMA directly induces the TF gene WASABI MAKER (WSB), which triggers MC differentiation. WSB and STOMATAL CARPENTER 1 (SCAP1, a stomatal lineage-specific direct FAMA target), synergistically promote GC differentiation. wsb mutants lacked MCs and the wsb scap1 double mutant lacked normal GCs. Evolutionary analyses revealed that WSB is conserved across stomatous angiosperms. We propose that the conserved and reduced transcriptional FAMA–WSB module was co-opted before evolving to induce MC differentiation.
ZBTB16/PLZF regulates juvenile spermatogonial stem cell development through an extensive transcription factor poising network
Spermatogonial stem cells balance self-renewal with differentiation and spermatogenesis to ensure continuous sperm production. Here, we identify roles for the transcription factor zinc finger and BTB domain-containing protein 16 (ZBTB16; also known as promyelocytic leukemia zinc finger (PLZF)) in juvenile mouse undifferentiated spermatogonia (uSPG) in promoting self-renewal and cell-cycle progression to maintain uSPG and transit-amplifying states. Notably, ZBTB16, Spalt-like transcription factor 4 (SALL4) and SRY-box transcription factor 3 (SOX3) colocalize at over 12,000 promoters regulating uSPG and meiosis. These regions largely share broad histone 3 methylation and acetylation (H3K4me3 and H3K27ac), DNA hypomethylation, RNA polymerase II (RNAPol2) and often CCCTC-binding factor (CTCF). Hi-C analyses show robust three-dimensional physical interactions among these cobound promoters, suggesting the existence of a transcription factor and higher-order active chromatin interaction network within uSPG that poises meiotic promoters for subsequent activation. Conversely, these factors do not notably occupy germline-specific promoters driving spermiogenesis, which instead lack promoter–promoter physical interactions and bear DNA hypermethylation, even when active. Overall, ZBTB16 promotes uSPG cell-cycle progression and colocalizes with SALL4, SOX3, CTCF and RNAPol2 to help establish an extensive and interactive chromatin poising network.
Rice transcription factor bHLH25 confers resistance to multiple diseases by sensing H2O2
Hydrogen peroxide (H2O2) is a ubiquitous signal regulating many biological processes, including innate immunity, in all eukaryotes. However, it remains largely unknown that how transcription factors directly sense H2O2 in eukaryotes. Here, we report that rice basic/helix-loop-helix transcription factor bHLH25 directly senses H2O2 to confer resistance to multiple diseases caused by fungi or bacteria. Upon pathogen attack, rice plants increase the production of H2O2, which directly oxidizes bHLH25 at methionine 256 in the nucleus. Oxidized bHLH25 represses miR397b expression to activate lignin biosynthesis for plant cell wall reinforcement, preventing pathogens from penetrating plant cells. Lignin biosynthesis consumes H2O2 causing accumulation of non-oxidized bHLH25. Non-oxidized bHLH25 switches to promote the expression of Copalyl Diphosphate Synthase 2 (CPS2), which increases phytoalexin biosynthesis to inhibit expansion of pathogens that escape into plants. This oxidization/non-oxidation status change of bHLH25 allows plants to maintain H2O2, lignin and phytoalexin at optimized levels to effectively fight against pathogens and prevents these three molecules from over-accumulation that harms plants. Thus, our discovery reveals a novel mechanism by which a single protein promotes two independent defense pathways against pathogens. Importantly, the bHLH25 orthologues from available plant genomes all contain a conserved M256-like methionine suggesting the broad existence of this mechanism in the plant kingdom. Moreover, this Met-oxidation mechanism may also be employed by other eukaryotic transcription factors to sense H2O2 to change functions.
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