Gomez Roldan MV, Yan Y, Du Y
… +12 more, Charlot F, Perroud PF, Calbry J, Griess O, Verdenaud M, Marcel F, Citerne S, Tran J, Ohad N, Coudert Y, Nogué F, Bendahmane A
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42372131
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The sexual life cycle of bryophytes and vascular plants, the two extant lineages of land plants, is dominated by a gametophytic and a sporophytic phase, respectively. Body plan diversification in these two phases has fol...The sexual life cycle of bryophytes and vascular plants, the two extant lineages of land plants, is dominated by a gametophytic and a sporophytic phase, respectively. Body plan diversification in these two phases has followed separate evolutionary trajectories in both lineages. However, how evolutionary conserved gene families have accompanied body plan diversification remains poorly understood. WIP transcription factors are conserved in land plants, and their function has been associated with root and flower development in angiosperms. Here, we dissect the function of Pp and Pp genes in a model bryophyte, the moss . We demonstrate that Pps are expressed during both phases of the life cycle and regulate specific developmental processes. In the gametophytic phase, Pps promote the chloronema-to-caulonema transition, but restrict gametophore development. In the sporophytic phase, Pp prevent polysety, the formation of multiple sporogonia. RNA-seq, DAP-seq, and hormone analysis revealed that both and proteins act by controlling auxin homeostasis. Interspecies complementation experiments revealed that Pps are partially able to substitute At molecular function in Arabidopsis root and seeds. Our findings demonstrate that WIPs control developmental progression in both phases of the land plant life cycle through an evolutionarily conserved molecular function.
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42372128
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Wildfire smoke poses a growing global health risk, largely from fine particulate matter (PM) emissions. Prescribed fires, which are critical for maintaining resilient forests in many locations, can also reduce wildfire e...Wildfire smoke poses a growing global health risk, largely from fine particulate matter (PM) emissions. Prescribed fires, which are critical for maintaining resilient forests in many locations, can also reduce wildfire emissions in treated areas that later burn. However, prescribed fires also produce smoke, creating a tradeoff in their net impact on PM emissions. We develop a mathematical framework showing that, under most current conditions globally, prescribed fire emissions are rarely offset by reduced wildfire emissions and therefore increase PM emissions overall. An analysis of 73 prior study sites reveals that reported net emission reductions are often based on unrealistic assumptions, for example that all treatments are subsequently encountered by wildfire during their effective lifespan. Using empirically based estimates of expected encounter rates, prescribed fire increases net emissions at 99% of sites, with a median 10-year increase of 210% (IQR: 70 to 475%), and only 0.06 tons of wildfire emissions avoided per ton of prescribed fire emissions (IQR: 0.03 to 0.15). However, prescribed fires are intentionally conducted under favorable meteorological conditions, allowing smoke to disperse more safely than during wildfires. Thus, whether prescribed burning can reduce health risks while increasing emissions-and whether its emissions impact can be lowered beyond current practice-is a critical area for future study. Regardless, prescribed fires have multiple objectives and benefits; they remain essential for forest management and hazard reduction.
Eren MI, Bebber MR, Walker RS
… +2 more, Johnson CR, Buchanan B
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42372127
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Late Pleistocene North American foragers assigned to the Clovis culture have long been assumed to have hunted megafauna with the atlatl, which would have provided several advantages. Yet, we chronologically modeled radio...Late Pleistocene North American foragers assigned to the Clovis culture have long been assumed to have hunted megafauna with the atlatl, which would have provided several advantages. Yet, we chronologically modeled radiocarbon ages from preserved Holocene atlatls and show that Clovis atlatl use is not supported. If Clovis hunters did not use atlatl technology, then its emergence in the Americas during the early Holocene represents a case of technological convergent evolution analogous to atlatls in Late Pleistocene Europe. A further implication is if Clovis hunters used spears, javelins, or bow technology then models concerning megafaunal hunting need to be rethought given the distinct effectiveness, hunting risk, and tactics associated with these weapons.
Guan J, Santer BD, Wang P
… +9 more, Fu Q, Garcia RR, Li Y, Stone K, Kinnison DE, Zhang J, Chiodo G, Lamarque JF, Solomon S
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42372126
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The Antarctic ozone hole was first reported in 1985, and small ozone losses at the global scale were also observed in the late 1980s. The combination of field and laboratory measurements, together with modeling, quickly...The Antarctic ozone hole was first reported in 1985, and small ozone losses at the global scale were also observed in the late 1980s. The combination of field and laboratory measurements, together with modeling, quickly established anthropogenic chlorofluorocarbons (CFCs) as the cause of both the Antarctic and global ozone depletion. However, when, where, and why the earliest ozone depletion could have been detected has not been determined. Here, we conduct a thought experiment to investigate when human-induced ozone depletion could have first been detectable, assuming the availability of accurate stratospheric ozone observations from 1950 onward. We find that human-caused ozone depletion was likely identifiable as early as 1957 in the tropical upper stratosphere. This region's low internal variability enables the earliest detection of the anthropogenic signal, even though tropical ozone losses in the upper stratosphere were smaller than those in higher-latitude regions. Our results highlight the key role of considering both internal variability ("noise") and the forced response ("signal") in detection studies. Further, while CFCs are widely recognized as the primary drivers of current ozone depletion, we find that early ozone loss was primarily caused by human-made carbon tetrachloride (CCl), used mainly as a solvent. These findings suggest that a clear human influence on the stratospheric ozone layer began nearly 70 y ago, even before substantial emissions of CFCs from spray cans or air conditioning.
Lindeman I, Officer A, Dahal-Koirala S
… +6 more, Risnes LF, Hjort R, Lundin KEA, Ness-Jensen E, Watson CT, Sollid LM
Proc Natl Acad Sci U S A
· 2026 Jun · PMID 42361043
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Polymorphisms of human leukocyte antigen (HLA) genes confer risks for human diseases. Predisposing effects related to T cell receptor (TCR) recognition of peptide-HLA can be selection of TCR repertoire and/or preferentia...Polymorphisms of human leukocyte antigen (HLA) genes confer risks for human diseases. Predisposing effects related to T cell receptor (TCR) recognition of peptide-HLA can be selection of TCR repertoire and/or preferential presentation of disease-driving epitopes. In celiac disease (CeD), HLA-DQ2.5 predisposes by presenting gluten peptides to CD4 T cells that typically employ stereotyped TCRs. Here, we analyzed whether genetic variants within the HLA and TR loci shape the naive TCR repertoire. We sequenced the αβ TCR repertoires of naive CD4 T cells of 103 CeD subjects and 103 controls and performed gene usage quantitative trait loci analyses. The naive CD4 TCR repertoire was significantly affected by TRA, TRB, and in particular HLA polymorphisms. The presence of HLA-DQ2.5 influenced the TCR repertoire, resulting in significant enrichment of TCR genes being involved in recognition of gluten epitopes in the repertoires of CeD subjects versus controls. HLA thus affects disease risk by selection of a disease-relevant TCR repertoire.
Proc Natl Acad Sci U S A
· 2026 Jun · PMID 42361042
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Understanding how mechanical, thermodynamic, and acoustic properties emerge in fluid-saturated nanoporous materials remains a major challenge due to the breakdown of classical continuum assumptions at molecular length sc...Understanding how mechanical, thermodynamic, and acoustic properties emerge in fluid-saturated nanoporous materials remains a major challenge due to the breakdown of classical continuum assumptions at molecular length scales. Here, we present a multiscale framework that extends linear chemo-poroelasticity theory to describe the coupled response of nanoporous solids and confined fluids to mechanical wave excitation. The effective poromechanical parameters-elasticity and stress-chemistry coupling tensors, scalar chemistry modulus, and fluid mobility tensor-are computed from atomistic simulations of methane adsorption and transport in a prototypical zeolite. These simulation-informed parameters are then embedded in a continuum model of mechanical wave propagation. This integrated approach enables the prediction of the effective wave speeds and attenuation as a function of frequency, fluid loading, and nanopore-scale structure. The methodology provides a physically grounded path for linking molecular interactions to macroscopic acoustic and elastic response. In turn, this framework offers opportunities for designing nanoporous materials with tailored transport, mechanical, and acoustical properties-particularly in the emerging field of nanoscale acoustics.
Ozaki E, Aktas S, Mulfaul K
… +12 more, Brennan K, Roubeix C, Palko S, Robb K, Ou Yang TH, Schanne-Klein MC, Toidze A, Watson A, Cahill M, Westenskow PD, Feenstra D, Doyle SL
Proc Natl Acad Sci U S A
· 2026 Jun · PMID 42361041
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Fibrosis is the end-stage of a maladaptive process that occurs when the body's normal wound-healing strategy becomes dysregulated. Subretinal fibrosis is the end stage of neovascular age-related macular degeneration (nAM...Fibrosis is the end-stage of a maladaptive process that occurs when the body's normal wound-healing strategy becomes dysregulated. Subretinal fibrosis is the end stage of neovascular age-related macular degeneration (nAMD), the most common cause of central vision loss in people over the age of 50. The cellular sources of excess extracellular matrix (ECM) contributing to subretinal fibrosis are unknown, as is the heterogeneity of cells involved in the fibrotic process. Here we identify cells contributing to subretinal fibrosis by using -YFP reporter mice to noninvasively image collagen production in real-time in vivo in two disease models, 1) a resolving retinal injury model and 2) a fibrotic model of subretinal disease. We create a collagen-producing eye cell atlas for subretinal injury and demonstrate subretinal fibroblast heterogeneity in healthy, resolving, and fibrotic tissue. We identify distinct molecular characteristics of general repair/resolving fibroblast populations versus pathogenic pro-fibrotic collagen-producing fibroblasts. Integration of this collagen-producing eye cell atlas with a published collagen-producing lung cell atlas shows conserved pro-fibrotic fibroblasts in both organs, yet also uncovers tissue-specific fibroblast populations unique to subretinal fibrosis. A fibroblast population significantly expands in subretinal fibrosis that expresses the highest levels of collagens and distinctively expresses ECM components , and . Immunolabeling of mouse and human-donor eye tissue support the fibroblastic expression and perivascular location of periostin as clearly distinguishing between bona fide fibrosis and early disease in nAMD. Our collagen-producing eye cell atlas is a valuable resource for studying distinct fibroblast subsets in homeostasis, early injury, and fibrosis.
Proc Natl Acad Sci U S A
· 2026 Jun · PMID 42361040
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In this paper, we study solid tori in contact manifolds. Specifically, we study the contact width of a knot type and give criteria for when it can be explicitly computed. We also prove there are many "nonthickenable" tor...In this paper, we study solid tori in contact manifolds. Specifically, we study the contact width of a knot type and give criteria for when it can be explicitly computed. We also prove there are many "nonthickenable" tori in many knot types. These tori are frequently essential in the study of Legendrian and transverse knot theory and tight contact structures on manifolds obtained by surgery on the knot. Previously, nonthickenable tori have only been observed for iterated torus knots in [Formula: see text] and were thought to be rare. We show that they are quite common, exist in other manifolds, and even for a hyperbolic knot in [Formula: see text]. We also make and highlight several conjectures about the general nature of knots in contact manifolds.
Proc Natl Acad Sci U S A
· 2026 Jun · PMID 42361039
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Evolutionary adaptation is often visualized as a population's stochastic climb toward the top of a fitness landscape. While there exist approaches to design or synthetically evolve proteins into desired structures, there...Evolutionary adaptation is often visualized as a population's stochastic climb toward the top of a fitness landscape. While there exist approaches to design or synthetically evolve proteins into desired structures, there is a lack of methodology for designing, tuning, and quantitatively reshaping the fitness landscapes themselves on which protein evolution takes place. Here, we introduce foundational principles of fitness landscape design (FLD) to customize the structural peaks and valleys of biophysical fitness landscapes with quantitative accuracy, offering robust control of long-term evolutionary outcomes. Our FLD algorithms use stochastic optimization of a chemically derived biophysical fitness model to consistently discover optimal antibody ensembles which force a target protein to evolve according to a user-specified target fitness landscape. We then apply FLD to suppress the fitnesses of two SARS-CoV-2 genotype neutral networks and to discover proactive vaccines that preemptively restrict escape variant fitness trajectories before they arise.
Broutzakis G, Pyrris Y, Akrani I
… +4 more, Neuhaus A, Mikros E, Diallinas G, Gatsogiannis C
Proc Natl Acad Sci U S A
· 2026 Jun · PMID 42361038
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Members of the nucleobase ascorbate transporter (NAT) family (SLC23) are elevator-type transporters that are responsible for the uptake of nucleobases and ascorbate. In fungi, NAT members are also responsible for the spe...Members of the nucleobase ascorbate transporter (NAT) family (SLC23) are elevator-type transporters that are responsible for the uptake of nucleobases and ascorbate. In fungi, NAT members are also responsible for the specific uptake of antifungal nucleobase analogues, such as oxypurinol, allopurinol, or 8-azaguanine. Here, we report nearly full-length cryo-EM structures of UapA, a high-affinity purine transporter from the model fungus , in inward-facing apo- and substrate-loaded conformations at 2.06 to 3.5 Å in detergent and lipid nanodiscs. The high-resolution structures reveal the role of water molecules and lipids in substrate binding, specificity, transporter dimerization, and activity. Notably, the N-tail of UapA is found to be structured, interacting with both the core and scaffold domains, which in combination with functional data suggests a dual role in trafficking and transport dynamics. Overall, our study provides unprecedented structural and functional insights into an elevator-type fungal transporter, which may well contribute to the exploitation of NAT transporters as specific gateways for targeted pharmacological antifungal approaches.
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42361030
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Proficiency testing is widely used to assess expertise in medicine, engineering, and other high-stakes fields. In forensic science, such tests are often cited in court as evidence that pattern-comparison methods are accu...Proficiency testing is widely used to assess expertise in medicine, engineering, and other high-stakes fields. In forensic science, such tests are often cited in court as evidence that pattern-comparison methods are accurate and reliable. Yet, the scientific value of proficiency testing depends on test design, scoring rules, and the extent to which results support valid inferences about real-world performance. A recent proficiency test of forensic firearm identification-the comparison of bullets and cartridge cases to determine whether they were fired from a particular gun-reported a false-positive error rate of nearly 20%. The broader significance of that result extends beyond the reported figure. We identify several limitations that can arise in forensic proficiency testing: use of items that may not reflect casework difficulty, reliance on consensus scoring rather than independently verified ground truth, inconsistent treatment of inconclusive responses, variation in test materials across examinees, and procedures vulnerable to contextual bias, including nonblind verification. These features make it difficult to distinguish examiner performance from properties of the test itself and weaken claims that reported scores estimate operational error rates. Properly constructed tests could measure individual differences in performance, identify sources of error, evaluate decision thresholds, and provide courts with more meaningful evidence about reliability. Although our focus is on firearms, these challenges extend to other pattern-comparison disciplines, including fingerprints and handwriting. We conclude that comprehensive, evidence-based reform of forensic proficiency testing is warranted.
Proc Natl Acad Sci U S A
· 2026 Jun · PMID 42348620
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Predicting the human burden of vector-borne diseases from limited surveillance data remains a major challenge, particularly in the presence of nonlinear transmission dynamics and delayed effects arising from vector ecolo...Predicting the human burden of vector-borne diseases from limited surveillance data remains a major challenge, particularly in the presence of nonlinear transmission dynamics and delayed effects arising from vector ecology and human behavior. We develop a data-driven framework based on an extension of Sparse Identification of Nonlinear Dynamics to systems with distributed memory, enabling discovery of transmission mechanisms directly from time series data. Using severe fever with thrombocytopenia syndrome as a case study, we show that this approach can uncover key features of tick-borne disease dynamics using only human incidence and local temperature data, without imposing predefined assumptions on human case reporting. We further ascertain the robustness of the recovered incidence-temperature model by integrating it with mechanistically derived tick-host covariates, showing that the forecasting ability does not improve. This suggests that the proposed core data-driven model already delivers strong predictions. The framework also allows for systematic sensitivity analysis of memory kernels and behavioral parameters. Although the approach prioritizes predictive accuracy over mechanistic transparency, it yields sparse, interpretable integral representations suitable for epidemiological forecasting. This methodology provides a scalable strategy for forecasting vector-borne disease risk and informing public health decision-making under data limitations.
Proc Natl Acad Sci U S A
· 2026 Jun · PMID 42348619
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The share of the world population living in cities with more than one million people rose from 11% in 1975 to 24% in 2025 (our estimates). Will this trend toward greater concentration in large cities continue or level of...The share of the world population living in cities with more than one million people rose from 11% in 1975 to 24% in 2025 (our estimates). Will this trend toward greater concentration in large cities continue or level off? We introduce two new city population datasets that use consistent city definitions across countries and over time. The first covers the world between 1975 and 2025, using satellite imagery. The second covers the United States between 1850 and 2020, using census microdata. We find that urban growth follows a characteristic life cycle. In the early stages of a country's urbanization process, large cities grow faster than smaller ones. At later stages, growth rates equalize across sizes. We use this life cycle to project future population concentration in large cities. Our projections suggest that 38% of the world population will be living in cities with more than one million people by 2100. This estimate is higher than the 33% implied by the well-known theory of proportional growth, but lower than the 42% obtained by extrapolating current trends.
Proc Natl Acad Sci U S A
· 2026 Jun · PMID 42348618
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The various slip behaviors of the subduction megathrust fault, including deadly megathrust earthquakes, are depth-dependent. Yet, we do not know what causes this depth dependence, in part due to variability between subdu...The various slip behaviors of the subduction megathrust fault, including deadly megathrust earthquakes, are depth-dependent. Yet, we do not know what causes this depth dependence, in part due to variability between subduction zone thermal structures and lithological inputs. Here, we investigate controls on the nucleation depths of great earthquakes (Mw [Formula: see text] 8) and the deeper extent of seismogenesis. To do so, we create rheologic strength envelopes for six subduction zones using published constitutive relations for subducting lithologies and regional thermal models. We then compare the strength envelopes to local plate interface earthquake depths. Our synthesis shows that subducted sediments undergo a transition from frictional to predominantly viscous deformation near [Formula: see text]C a transition that correlates with the maximum nucleation depths of great earthquakes at 20 to 30 km. However, smaller plate interface earthquakes ([Formula: see text] Mw [Formula: see text] 8) continue to nucleate below this depth, and the maximum earthquake size decreases until the base of the seismogenic zone at 40 to 60 km depth and [Formula: see text]500 °C. We evaluate potential causes of seismicity below the onset of viscous deformation in these now metasediments, and conclude that the presence of lithologic heterogeneities that are loaded to frictional failure by viscously deforming metasediments is most plausible. Thus, we propose that great earthquakes can nucleate and grow into large events where all lithologies are frictional. However, the base of the seismogenic zone is deeper than the onset of viscous deformation in metasediments, which limits the growth of earthquakes into large events, and here seismicity reflects the existence and size of heterogeneity along the plate interface.
Liang G, Nguyen HV, Zhu J
… +19 more, Tiriac H, Zafar H, Cao DY, Estepa G, Nelson DC, Dai Y, Oh TG, Liddle C, Yu RT, Hunter T, Engle D, Shaw R, Lowy AM, Fan W, Truitt ML, Atkins AR, Johnson JA, Downes M, Evans RM
Proc Natl Acad Sci U S A
· 2026 Jun · PMID 42348617
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The DNA damage response (DDR) is critical for pancreatic ductal adenocarcinoma (PDAC) development and therapeutic responses, including to genotoxic agents. While epigenetic modulators have been shown to contribute to the...The DNA damage response (DDR) is critical for pancreatic ductal adenocarcinoma (PDAC) development and therapeutic responses, including to genotoxic agents. While epigenetic modulators have been shown to contribute to the DDR, how chromatin regulation dictates responses to DNA damage in PDAC remains incompletely understood. Here, we identify Class I histone deacetylases (HDACs) as critical regulators of the DDR. HDAC1/2 direct the genomic distribution of H3K27ac, ensuring sufficient BRD4 and RNA polymerase II (Pol II) occupancy at DDR gene promoters. HDAC inhibition by entinostat shifts the balance of H3K27 acetylation preferentially toward intergenic regions, diverting BRD4 and Pol II from promoters, thereby suppressing DDR gene expression. In line with this, HDAC inhibition heightens DNA damage and sensitizes PDAC to diverse DNA-damaging and DDR-targeting agents. Since the clinical development of HDAC inhibitors has been limited by systemic toxicity, we developed bottlebrush prodrug (BPD) nanoparticles for tumor-selective entinostat delivery. Entinostat-BPD achieved tumor-specific HDAC inhibition while displaying potent efficacy and reduced systemic toxicity. These findings reveal an HDAC-dependent DDR vulnerability and offer combinational and precision targeting strategies to facilitate clinical translation and improve PDAC patient outcomes.
Proc Natl Acad Sci U S A
· 2026 Jun · PMID 42348616
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Meiotic recombination is highly conserved across vertebrates and plays an essential role in ensuring chromosomal segmentation and generating genomic variation. However, species employ two strikingly different mechanisms...Meiotic recombination is highly conserved across vertebrates and plays an essential role in ensuring chromosomal segmentation and generating genomic variation. However, species employ two strikingly different mechanisms to guide recombination. In most mammals, recombination hotspot locations are determined by the protein PRDM9, which binds specific DNA sequence motifs. These motifs are rapidly eroded by biased gene conversion, rendering this mechanism self-destructive and evolutionarily transient. In contrast, birds initiate recombination at open chromatin regions independently of sequence motifs, producing self-preserving and evolutionarily stable recombination hotspots. Some species use both types of hotspots simultaneously, raising the unresolved question of why PRDM9-guided hotspots persist alongside a robust alternative. Here, we address this problem using a population genetic model that explicitly considers competition between PRDM9-guided and non-PRDM9-guided recombination hotspots. We show that non-PRDM9-guided hotspots are generally favored because, lacking sequence specificity, they generate more crossovers required for proper chromosome segregation. However, PRDM9-guided hotspots can overcome this disadvantage when simultaneous binding of both homologous chromosomes (symmetric binding) is more likely to resolve as crossovers than binding of a single homolog (asymmetric binding). Although PRDM9 reduces overall crossover rate, its sequence specificity increases the probability of symmetric binding within hotspots, creating a trade-off that can favor PRDM9 under specific selection regimes. Our model predicts that PRDM9-dependent species are particularly sensitive to disruptions of symmetric binding, whereas species lacking PRDM9 are more vulnerable to complete crossover failure. Intermediate regimes allow stable coexistence of both hotspot types.
Probst CM, Yanco S, Clark I
… +5 more, Ziebell M, Fuirst M, Mackenzie SA, Ibáñez I, Weeks BC
Proc Natl Acad Sci U S A
· 2026 Jun · PMID 42341052
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Biodiversity is declining, with cascading effects of defaunation expected across trophic levels. Widespread population declines may drive general biotic responses to global change and determine their fitness effects. We...Biodiversity is declining, with cascading effects of defaunation expected across trophic levels. Widespread population declines may drive general biotic responses to global change and determine their fitness effects. We find that a 62% decrease in insect biomass over a half-century altered the morphology, survival, and breeding phenology of an aerial insectivore, the tree swallow (). Low-insect years resulted in decreased tree swallow body mass, with the fitness landscape shifting to favor smaller individuals. Earlier, more temporally variable, and less-pronounced peaks in insect abundance eroded the benefits of phenological synchronization across trophic levels. This phenomenon-which we term trophic decay-led to advantageous phenological mismatch in low-insect years. Our results suggest classic responses to climate change must be evaluated within the context of widespread resource declines.
Zheng F, Cao Y, Chen H
… +10 more, Yan L, Lv F, Huang Y, Chen M, Su L, Liu Z, Huang Y, Pham T, Xu X, Lin X
Proc Natl Acad Sci U S A
· 2026 Jun · PMID 42341051
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Meiosis is a hallmark of sexual reproduction. Although the core meiotic machinery is evolutionarily conserved from unicellular yeasts to Metazoan, the key regulators responsible for initiating meiosis vary across species...Meiosis is a hallmark of sexual reproduction. Although the core meiotic machinery is evolutionarily conserved from unicellular yeasts to Metazoan, the key regulators responsible for initiating meiosis vary across species and remain largely unidentified in major eukaryotic lineages, including the major phylum Basidiomycota in the Kingdom Fungi. The basidiomycete fungus is a critical pathogen listed by the World Health Organization that causes life-threatening meningoencephalitis worldwide. Meiosis not only indirectly facilitates cryptococcal pathogenicity through generating genetically diverse spores but also directly contributes to host adaptation and disease progression. Here, we identified a novel transcription factor Msd1 that is responsible for activating meiosis in . Deletion of impaired multiple sexual development events and strikingly abolished meiosis and subsequent sporogenesis (gametogenesis). Conversely, overexpression of alone is sufficient to drive meiosis and the formation of meiotic spores, even in the absence of the external mating-inducing cues or when the mating pathway is genetically inactivated. Mechanistically, we demonstrated that Msd1 initiates meiotic entry by targeting two interconnected pathways. First, Msd1 activates the transcription of multiple evolutionarily conserved core meiosis-specific genes such as meiotic recombinase Dmc1. Second, Msd1 activates two RNA-binding proteins, Csa1 and Csa2, which ensure spatiotemporal expression of the aforementioned meiosis-specific genes to drive meiosis and sporogenesis. Collectively, our findings demonstrate that meiosis and the sequential sexual development events are spatiotemporally orchestrated by the master regulator Msd1, and is the first reported regulator initiating meiotic entry in a basidiomycete fungus.