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PubMed2026

Four-dimensional molecular mapping from a spatial snapshot reveals the dynamics of hair follicle organogenesis.

Understanding organ formation requires capturing molecular information simultaneously in three-dimensional (3D) space and across developmental time. To this end, we developed 3D DNase-Enhanced Expression Profiling (3DEEP), a tissue-clearing approach that removes genomic DNA to extend spatial transcriptomic profiling hundreds of microns into intact tissues. We applied 3DEEP to neonatal mouse skin, capturing hundreds of developing hair follicles across their organogenesis trajectory. Ordering follicles by molecularly inferred developmental age transformed this single spatial snapshot into a four-dimensional (3D + time) molecular map of organogenesis. This map revealed developmental dynamics spanning stem cell compartment stratification, emergence of new cell subtypes within the follicle, and cascading structural transformations leading to hair canal formation. Comparative analysis of Foxn1-deficient nude mice, a hairlessness model, revealed organ-wide changes in developmental dynamics, including delayed molecular progression, reduced coordination, and increased developmental instability, preceding overt structural defects. This work demonstrates how deep-tissue spatial transcriptomics can uncover hidden dynamics of organ formation.

Animals↗
PubMed2025

KLHL13 functional defects cause neurodevelopmental disorder in humans that can be rescued via inhibition of AURKB in cellular and animal models.

PURPOSE: Neurodevelopmental disorders (NDDs) are characterized by limitations in brain development. This study aims to determine the genetic causes of NDD in humans. METHODS: Exome sequencing was used to detect genetic variants of KLHL13, which encodes Kelch like protein 13 (KLHL13), in four families segregating in an X-linked pattern. In silico protein modeling and overexpression in heterologous cells were used to determine the variant's impact. klhl13 loss of function was modeled in zebrafish, followed by rescue studies using human KLHL13 messenger RNA (mRNA) and an Aurora Kinase B (AURKB) inhibitor. RESULTS: We found one frameshift and three missense hemizygous variants of KLHL13 in individuals exhibiting NDD characteristics, such as intellectual disability (ID) and macrocephaly. Three-dimensional protein modeling simulation predicted the alteration of the KLHL13 protein folding for missense variants. Overexpression of NDD-associated variants in HEK293T cells revealed a significant impact on KLHL13-mediated cell-cycle regulation during mitosis, leading to genomic instability. Knocking down klhl13 in zebrafish resulted in developmental deficits, which were rescued by coinjection of human KLHL13WT messenger RNA but not by transcript encoding NDD variants. Treatment with AURKB selective inhibitor AZD1152-HQPA rescued genomic stability in heterologous cells and neurobehavioral deficits in zebrafish. CONCLUSION: Our results implicate KLHL13-mediated AURKB regulation as a significant contributor to NDD in humans. Inhibiting AURKB activity could serve as a potential therapeutic approach to improve brain development and cognitive function.

Humans↗
PubMed2026

Timing of adverse childhood experiences shapes epigenetic ageing and life-history outcomes.

Early-life adversity is widely linked to accelerated biological ageing, yet it remains unclear whether such associations reflect exposure during sensitive developmental periods, the cumulative burden of exposures, or temporal proximity to later outcomes. Here, we leverage life-history theory and a life course framework to nuance how the timing of adverse childhood experiences (ACEs) becomes biologically embedded through epigenetic ageing. Using longitudinal data from the Future of Families and Child Wellbeing Study (N=1,974), we apply statistical learning and structured life course modelling to test sensitive period, cumulative risk, and recency hypotheses across multiple domains of adversity (poverty, instability, deprivation, and maltreatment). We find that adversity exposure during specific developmental periods, rather than cumulative burden or recent exposure, are most strongly associated with epigenetic age acceleration in late childhood ([Formula: see text]=0.003). Moreover, the timing and direction of these effects vary by adversity type. Epigenetic ageing is in turn associated with later health-related risks ([Formula: see text]=0.29, SE=0.06; [Formula: see text]=1.62, SE=0.27) and demographic behaviour ([Formula: see text]=0.21, SE=0.08; [Formula: see text]=0.22, SE=0.11), and further mediates the association between ACEs and outcomes in young adulthood, particularly for BMI ([Formula: see text]=0.003, SE=0.002, [Formula: see text]=11%). These findings demonstrate that childhood adversity may be linked to biological ageing in developmentally specific and domain-dependent ways, with certain developmental periods appearing more sensitive to adversity exposure than others.

Humans↗
PubMed2026

Variants leading to ELAVL2 haploinsufficiency cause a neurodevelopmental disorder with prominent cognitive, behavioral, and neurological features.

RNA-binding proteins (RBPs) regulate gene expression, and a number of RBPs have been implicated in brain function and behavior. Here, we report 16 individuals with a neurodevelopmental disorder and de novo heterozygous variants in ELAVL2, encoding an RBP not previously linked to Mendelian disease. Thirteen individuals were identified through GeneMatcher. Their ELAVL2 variants include two structural, five nonsense, and six missense variants, supporting haploinsufficiency as the primary disease mechanism. The cohort presented with developmental delay, intellectual disability, autism spectrum disorder, seizures, sleep problems, sensory processing issues, emotional instability, and difficulty with socialization. Three additional variants (two missense and one terminal exon truncation), each previously reported in a different large cohort study, were also included for follow-up investigations. We provide multiple lines of evidence linking variants in ELAVL2 to the observed neurodevelopmental and behavioral phenotypes. First, we show that common genetic variants in ELAVL2 are significantly associated with intelligence, motor development, sleep-related traits, and sociability in the general population. Drosophila loss-of-function models provide further independent evidence for a conserved role in the regulation of seizure-like behavior, sensory processing, and sleep. Molecular studies confirm that some of the missense variants are deleterious, leading to decreased protein levels. Together, our integrative study combining Mendelian genetics, clinical and association studies, and animal and molecular modeling supports variants in ELAVL2 as a cause of a neurodevelopmental disorder, with haploinsufficiency as the disease mechanism, and identifies crucial roles of ELAVL2 in neuronal function, cognition, and behavior.

Humans↗
PubMed2025

Polygenic variants in DNA repair genes are associated with neurodevelopmental disorders, regression and increased burdens of somatic variants and short tandem repeat expansions.

PURPOSE: Developmental regression, characterized by the loss of acquired milestones, occurs in some individuals with neurodevelopmental disorders (NDDs); yet, its molecular basis remains unclear. Studies suggest that DNA damage repair (DDR) genes, such as FAN1, may protect against neurological dysfunction by modulating the somatic stability of short tandem repeats (STRs). This study explores the contribution of DDR gene variants in NDD cases presenting with regression. METHODS: We analyzed 1087 NDD patients, focusing on those carrying variants in DDR genes and presenting regression. We assessed the sensitivity to DNA damage using mitomycin C on lymphoblastoid cells. Somatic variants and STR expansions were evaluated through high-depth short-read genome sequencing. To further investigate the pathogenetic role of STR expansions, we performed long-read genome sequencing on the most severely affected proband. RESULTS: Probands with regression carried multiple DDR gene variants, several within the Fanconi anemia pathway. Their lymphoblastoid cells showed increased sensitivity to mitomycin C-induced cytotoxicity compared with parental and control samples. Probands with severe phenotypes and regression exhibited an accumulation of somatic variants and STR instability, enriched in neurodevelopmental genes. CONCLUSION: Our findings suggest that polygenic DDR gene variants may contribute to developmental regression in NDDs by promoting the accumulation of somatic variants and STR expansions.

Humans↗
PubMed2025

Pathogenic variants in MAEA disrupt DNA replication fork stability and are associated with developmental abnormalities in humans.

Replication stress (RS) poses a threat to genome stability and drives genomic rearrangements. The homologous recombination (HR) pathway repairs stalled replication forks (RFs) and prevents such instability. Through an E3 ubiquitin ligase screen aimed at identifying regulators of RAD51, we identified macrophage erythroblast attacher (MAEA), a core component of C-terminal to Lish (CTLH) E3 ubiquitin ligase complex, as a regulator of the HR pathway. Loss of MAEA impairs RAD51 recruitment at stalled RFs, leading to increased sensitivity to RS-inducing agents and excessive degradation of nascent DNA strands. Mechanistically, MAEA associates with and mediates the ubiquitylation of Ku80, enabling its removal from RF ends and facilitating the loading of RAD51. Notably, MAEA deficiency is associated with a developmental disorder involving microcephaly, craniofacial abnormalities, ocular defects, and heart malformations. Functional assays show that disease-linked MAEA variants (R34C, E349G, Y394D, and M396R) are defective in RS response. These findings establish MAEA as an essential factor in RF protection and genome integrity.

Humans↗
PubMed2026

Mirror worlds: The shared regulatory architecture of cell fate in development and cancer.

Lineage plasticity has emerged as a central mechanism through which cancer cells adapt to therapeutic pressure, evade immune surveillance, and acquire aggressive phenotypes. Although recognized across tumor types, the regulatory principles governing how cancer cells reprogram cellular identity remain incompletely understood. In this review, we propose that lineage plasticity in cancer reflects the redeployment of regulatory frameworks established during normal development. Rather than representing a stochastic byproduct of genomic instability, cancer plasticity frequently unfolds within gene regulatory architectures that also govern cell fate specification, lineage commitment, and controlled state transitions during embryogenesis and tissue homeostasis. Developmental transcription factors, including members of the SOX family, FOXA1, ASCL1, NKX2-1, and epithelial-mesenchymal transition regulators, function as lineage gatekeepers during development but are repurposed in cancer to destabilize lineage commitment and enable phenotypic switching. Similarly, epigenetic regulators that guide developmental trajectories, including chromatin remodeling complexes, Polycomb group proteins, and DNA methylation machinery, are frequently dysregulated or redistributed in tumors, altering the repression of lineage-stabilizing and alternative lineage programs and thereby weakening epigenetic barriers to lineage transitions. Together, these observations support a model in which development and cancer operate as mirror regulatory systems: one establishing and stabilizing cellular identity, the other exploiting the same regulatory architecture to permit adaptive reprogramming under selective pressure. We further discuss how emerging single-cell and spatial multi-omics technologies, integrated with artificial intelligence-based modeling, enable mapping of cell state landscapes and transitional trajectories, transforming lineage plasticity from a descriptive phenomenon into a measurable and predictable property of tumor evolution.

Humans↗
PubMed2026

Developmental regulation of progenitor aging shapes long-term intestinal homeostasis in Drosophila.

Aging causes disruption of tissue homeostasis, with stem cell exhaustion as a major hallmark. However, whether aging trajectories are established during development remains unexplored. Here, we demonstrate that genetic modulation of aging-associated pathways in larval adult midgut progenitors (AMPs) determines the trajectory of Drosophila adult intestinal homeostasis. Induction of aging-associated pathways in the AMPs results in aberrant proliferation, skewed differentiation, barrier dysfunction, and genomic instability. Ultimately, AMP islet architecture is destabilized and age-related molecular signatures are altered. In contrast, reversing aging-associated effects results in a decrease in the enteroendocrine population and the barrier is unaffected. Together, our findings demonstrate that aging-associated pathways are tightly regulated during early development and perturbation can hamper adult gut homeostasis, establishing AMPs as key developmental determinants.

Drosophila↗
PubMed2025

Developmental timing of index trauma exposure and accelerated epigenetic aging in United States military veterans.

Trauma exposure has been linked to accelerated GrimAge, an epigenetic biomarker of premature morbidity and mortality. Building on this evidence, the present study examined whether the type and timing of index trauma exposure are differentially associated with accelerated GrimAge. Participants were 873 European American male United States military Veterans from the National Health and Resilience in Veterans Study. We investigated associations between self-reported age at index trauma, index trauma type (interpersonal violence, non-interpersonal trauma, or loss/instability/other), and accelerated GrimAge, operationalized as GrimAge exceeding chronological age by five or more years. Results revealed that interpersonal violence was associated with three-fold greater odds of accelerated GrimAge compared to other trauma types. Age at index trauma was not independently associated with accelerated GrimAge. However, we observed a significant interaction between trauma type and its developmental timing, even after adjusting for index trauma recency, cumulative trauma burden, and other potential confounders. Specifically, Veterans who were older at the time of exposure to interpersonal violence or trauma involving loss or instability had higher odds of accelerated GrimAge. In contrast, exposure to non-interpersonal trauma was more strongly associated with accelerated GrimAge when it occurred at younger ages. These results indicate that trauma type and timing jointly influence epigenetic aging in Veterans, highlighting the need for tailored interventions that address specific trauma characteristics to reduce associated long-term health risks in this population.

Humans↗
PubMed2026

Mechanisms of Hexavalent Chromium-Induced Reproductive Toxicity: A Focus on the Ovary and Placenta.

Hexavalent Chromium (Cr(VI)) is a Group A carcinogen, mutagen, and teratogen. Cr(VI) has been used by more than 50 industries, and its contamination of drinking water is widespread across the United States (U.S.). Epidemiological data of women who lived in Willits, California, U.S., indicate that environmental exposure to Cr(VI) adversely affects pregnancy outcomes and the health of their immediate offspring, resulting in a low birth rate, pregnancy loss, and spontaneous abortion, and their children (F1 offspring) experienced birth defects. However, the molecular mechanisms behind Cr(VI)-induced reproductive and developmental toxicity are poorly understood. Cr(VI) enters cells through anion transporters and is rapidly reduced to Cr(III) by endogenous antioxidants within the cell. Cr(III) forms adducts with DNA, which can block DNA replication and transcription; abnormal repair can lead to DNA double-strand breaks, mutations, micronucleus formation, chromosomal abnormalities, and increased genomic instability. Cr(VI) induces oxidative stress via the Fenton reaction, generating free radicals, and depleting antioxidants, thereby promoting apoptosis via p53-dependent and independent pathways, resulting in follicular atresia and accelerated reproductive aging. Antioxidant supplementation with resveratrol, vitamin C, and edaravone mitigates Cr(VI) toxicity in the ovary. Cr(VI) disrupts meiosis in metaphase II oocytes by causing DNA strand breaks, altering F-actin dynamics, disturbing microtubules, and leading to chromosome missegregation. Gestational exposure to Cr(VI) also disrupts placental function through multiple mechanisms by targeting trophoblast lineages. The current review focuses on genotoxicity, oxidative stress, and other mechanisms by which Cr(VI) disrupts the female reproductive and endocrine systems, with particular emphasis on the ovary and placenta.

Hexavalent chromium↗
PubMed2026

Distinct STRIPAK subunits drive conserved and subunit-specific signaling programs in Cryptococcus neoformans.

The striatin-interacting phosphatase and kinase (STRIPAK) complex is a conserved protein phosphatase 2A (PP2A)-associated signaling hub that integrates kinase-phosphatase networks, yet its roles in human fungal pathogens remain poorly defined. Here, we dissected STRIPAK functions in the opportunistic pathogen Cryptococcus neoformans by combining genetic, genomic, virulence, and phosphoproteomic analyses across mutants lacking individual STRIPAK subunits. Loss of the core STRIPAK components via PPH22, FAR8, FAR9, or FAR11 mutations caused severe defects in growth, stress adaptation, cell cycle progression, and morphogenesis, accompanied by widespread aneuploidy and genome instability. In murine infection models, far11Δ strains were avirulent, whereas far9Δ mutants caused delayed but ultimately fatal disease and underwent host-associated genome remodeling, with recovered isolates exhibiting chromosome 11 amplification despite no consistent in vitro fitness advantage. In contrast, deletion of MOB3 produced a hypervirulent phenotype. mob3Δ cells exhibited enhanced transmigration across an in vitro blood-brain barrier model, increased survival in macrophages, and generated small-cell morphotypes, features associated with increased dissemination. Phosphoproteomic profiling revealed extensive and overlapping phosphorylation changes among core STRIPAK mutants, affecting pathways involved in signaling, cytoskeletal, cell cycle control, chromatin regulation, RNA metabolism, and stress responses. Conversely, mob3Δ mutants displayed a smaller, largely distinct phosphoproteomic signature. Network and functional enrichment analyses highlighted STRIPAK-dependent regulation of TORC2-associated signaling, MAPK/GTPase signaling, autophagy, nuclear transport, RNA processing, DNA replication, and ribosome biogenesis. Together, these findings establish STRIPAK as a coordinator of genome stability, morphological plasticity, stress adaptation, and virulence in C. neoformans, and demonstrate that individual STRIPAK subunits drive shared yet divergent signaling outputs that shape host-pathogen interactions.IMPORTANCEFungal pathogens must rapidly adapt their growth, morphology, and stress responses to survive within the host, requiring precise coordination of cellular signaling pathways. The conserved striatin-interacting phosphatase and kinase (STRIPAK) complex controls key developmental programs in eukaryotes, but its roles in fungal pathogenesis are not fully defined. We previously showed that STRIPAK is important for genome stability, development, and virulence in the opportunistic human fungal pathogen Cryptococcus neoformans. Here, we define how individual STRIPAK subunits differentially regulate fungal morphogenesis, genome plasticity, host adaptation, and virulence, revealing both shared and subunit-specific functions within this conserved signaling complex. Core STRIPAK mutants exhibit severe growth and stress-response defects and attenuation of virulence, whereas loss of the Mob3 subunit promotes hypervirulence by enhancing dissemination and persistence within the host. Phosphoproteomic profiling reveals that individual STRIPAK components exert shared yet distinct control over phosphorylation networks that shape host-pathogen interactions, establishing STRIPAK as a central signaling hub and a potential target for antifungal intervention.

Cryptococcus neoformans↗
PubMed2025

Deep clinical and genetic analysis of 17p13.3 region: 38 pediatric patients diagnosed using next-generation sequencing and literature review.

BACKGROUND: Chromosome 17p13.3 is a region of genomic instability associated with different neurodevelopmental diseases. The malformation spectrum of 17p13.3 microdeletions ranges from an isolated lissencephaly sequence to Miller-Dieker syndrome, while 17p13.3 microduplications result in autism, learning disabilities, microcephaly and other brain malformations. This study aims to provide a more comprehensive delineation of the clinical and genetic characteristics associated with 17p13.3 alterations. METHODS: We retrospectively analyzed the next-generation sequencing (NGS) data of more than 40 thousand patients from January 2016 to December 2021 and identified 38 pediatric patients with copy-number variations (CNVs) or single-nucleotide variations (SNVs) in 17p13.3 region. Published patients with CNVs in the 17p13.3 region were also collected and we performed a Chi-square test to compare the phenotype spectrum of microdeletions and microduplications. RESULTS: Among the 27 CNV patients, 20 patients with microdeletions and 7 patients with microduplications were found. PAFAH1B1 was the most frequently deleted gene and CRK was the most frequently duplicated gene. Affected genes in 11 SNV patients included PAFAH1B1 and PRPF8. Developmental delay was the most common abnormality detected in the 38 patients (29/38, 76.3%). Of note, Case 10 presented omphalocele and Case 23 presented scoliosis, webbed neck and bone cyst, all of which were unusual variant phenotypes in this region. The Chi-square test revealed that epilepsy, lissencephaly and short stature were statistically significant with microdeletions, while behavioral abnormalities and hand and foot abnormalities were significant with microduplications (p&#x2009;<&#x2009;0.01). CONCLUSIONS: While PAFAH1B1, YWHAE and CRK are associated with major phenotypes of 17p13.3, RTN4RL1 may be involved in white matter changes and HIC1 might contribute to the occurrence of omphalocele. This study provided a comprehensive understanding of genetic information and phenotype spectrum of the 17p13.3 region.

Humans↗