Search Results (99)

Long bone formation in vertebrates proceeds via endochondral ossification, a sequential process that begins with mesenchymal condensation, advances through cartilage anlage formation, and culminates in its replacement by mineralized bone. Recent advances in inducible lineage tracing and single-cell genomics have revealed that, rather than being a uniform event, mesenchymal condensation rapidly segregates into progenitor pools with distinct fates. Centrally located Sox9⁺/Fgfr3⁺ chondroprogenitors expand into the growth plate and metaphyseal stroma, peripheral Hes1⁺ boundary cells refine condensation via asymmetric division, and outer-layer Dlx5⁺ perichondrial cells generate the bone collar and cortical bone. Concurrently, dorsoventral polarity established by Wnt7a–Lmx1b and En1 ensures that dorsal progenitors retain positional identity throughout development. These lineage divergences integrate with signaling networks, including the Ihh–PTHrP, FGF, BMPs, and WNT/β-catenin networks, which impose temporal control over chondrocyte proliferation, hypertrophy, and vascular invasion. Perturbations in these programs, exemplified by mutations in Fgfr3, Sox9, and Dlx5, underlie region-specific skeletal dysplasias, such as achondroplasia, campomelic dysplasia, and split-hand/foot malformation, demonstrating the lasting impacts of embryonic patterning errors. Based on these insights, regenerative strategies are increasingly drawing upon developmental principles, with organoid cultures recapitulating ossification centers, biomimetic hydrogels engineered for spatiotemporal morphogen delivery, and stem cell- or exosome-based therapies harnessing developmental microRNA networks. By bridging developmental biology with biomaterials science, these approaches provide both a roadmap to unravel skeletal disorders and a blueprint for next-generation therapies to reconstruct functional bones with the precision of the embryonic blueprint. Full article

Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) is an RNA-binding protein known to play critical roles in metabolism, cell proliferation, and tumorigenesis. Although its involvement in muscle development has been documented in several species, the function of goose IGF2BP2 remains largely unexplored. In this study, we cloned and characterized the full-length cDNA and genomic DNA sequences of goose IGF2BP2. The cDNA is 2957 bp in length and contains a 1662 bp open reading frame encoding a 553-amino acid protein with five conserved RNA-binding domains. The genomic sequence spans 12,183 bp and consists of 12 exons and 11 introns. A total of 60 genetic variants were identified, including a deletion of a G base at position 2299 (g.2299delG) that results in a frameshift mutation. Expression analysis revealed high levels of IGF2BP2 mRNA in the liver, heart, and muscle tissues of female geese across embryonic (E25d), growing (A70d), and laying (L270d) stages, consistent with a potential role in muscle development (p < 0.05). Functionally, overexpression of IGF2BP2 in skeletal muscle satellite cells (SMSCs) was associated with significant changes in the expression of several genes linked to muscle development and signaling pathways, including upregulation of IGF1, EGFR, FGF19, BMP6, BMP2, ACVR1C and WNT5A and downregulation of MYBPC3, NODAL, HOXD13, TNXB, and ADD2 (Padj < 0.01). Furthermore, protein–protein interaction (PPI) network analysis of these genes suggests that IGF2BP2 may coordinate key genes, contributing to its potential role in skeletal muscle development in geese. Full article

Inherited retinal degenerations (IRDs), driven by pathogenic mutations, often involve primary dysfunction of the retinal pigment epithelium (RPE)—a pathogenic feature shared with atrophic age-related macular degeneration (aAMD), despite aAMD’s multifactorial etiology. Prominin-1 (Prom1), traditionally linked to photoreceptor pathology, has an unclear role in RPE homeostasis. We assessed Prom1 expression in C57BL/6J mouse retina sections and RPE flat mounts using immunohistochemistry and generated Prom1-knockout (KO) mouse RPE cells via CRISPR/Cas9. Bulk RNA sequencing with DESeq2 and gene set enrichment analysis (GSEA) revealed Prom1-regulated pathways. Prom1-KO cells exhibited upregulation of Grem1, Slc7a11, Serpine2, Il1r1, and IL33 and downregulation of Ablim1, Cldn2, IGFBP-2, BMP3, and OGN. Hallmark pathway interrogation identified reduced expression of PINK1 (mitophagy) and MerTK (phagocytosis), implicating defects in mitochondrial quality control and outer segment clearance. Enrichment analysis revealed activation of E2F/MYC targets, mTORC1 signaling, oxidative phosphorylation, and TNFα/NF-κB signaling, alongside suppression of apical junctions, bile acid metabolism, and Epithelial-Mesenchymal Transition (EMT) pathways. These findings suggest Prom1 safeguards RPE integrity by modulating stress responses, mitochondrial turnover, phagocytosis, metabolism, and junctional stability. Our study uncovers Prom1-dependent signaling networks, providing mechanistic insights into RPE degeneration relevant to both IRD and aAMD, and highlights potential therapeutic targets for preserving retinal health. Full article

Arteriovenous malformations (AVMs) are fast-flow vascular malformations formed by direct artery-to-vein shunts without an intervening capillary bed, which increases the risk of hemorrhage and organ-specific damage. A synthesis of recent advances shows that AVMs arise from interplay between germline susceptibility (ENG, ACVRL1, SMAD4, RASA1, EPHB4), somatic mosaicism (KRAS, MAP2K1, PIK3CA), perturbed signaling (TGF-β/BMP, Notch, VEGF, PI3K/AKT, RAS/MAPK), hemodynamic stress, and inflammation. Multimodal imaging—digital subtraction angiography (DSA), MRI/MRA with perfusion and susceptibility sequences, CTA, Doppler ultrasound, and 3D rotational angiography—underpins diagnosis and risk stratification, while arterial spin labeling and 4D flow techniques refine hemodynamic assessment. Management is individualized and multidisciplinary, combining endovascular embolization, microsurgical resection, and stereotactic radiosurgery (SRS); a non-surgical approach and monitoring remain reasonable for some asymptomatic AVMs. Device and technique innovations (detachable-tip microcatheters, pressure-cooker approaches, and newer liquid embolics such as PHIL and Squid) have broadened candidacy, and precision-medicine strategies, including pathway-targeted pharmacotherapy, are emerging for syndromic and somatic-mutation–driven AVMs. Animal models and computational/radiomics tools increasingly guide hypothesis generation and treatment selection. We outline practical updates and future priorities: integrated genomic-imaging risk scores, genotype-informed medical therapy, rational hybrid sequencing, and long-term outcome standards focused on hemorrhage prevention and quality of life. Full article

Brain arteriovenous malformations (bAVMs) consist of a tangled nidus of abnormal dilated vessels characterized by direct connections between arteries and veins that lack an intervening capillary bed, creating a high-to-low flow pressure system that is predisposed to spontaneous hemorrhage with significant associated neurologic morbidity and mortality. Treatment options for bAVMs include the following: surgical resection, intravascular embolization to obliterate blood flow through the AVM, and radiosurgery. Understanding the molecular mechanisms of bAVM formation and factors that predispose it to hemorrhage can lead to novel treatments that can improve the prognosis for patients. This review summarizes emerging insights into the complex and dynamic molecular mechanisms of bAVMs. Dysregulation in key VEGF, TGF-β/BMP9/10–ENG–ALK1–SMAD4, Notch, and MAPK/ERK signaling pathways drive abnormal angiogenesis in both syndromic and sporadic forms, with KRAS/BRAF/MAPK21 mutations specifically linked to the latter. Advances in bAVM-induced animal models have corroborated many of the genetic profiles found in humans, and they continue to provide novel insights into bAVM mechanisms. Collectively, these mechanistic findings are guiding translational advances, with targeted therapies and liquid biopsy approaches emerging as avenues for precision treatment and improved patient outcomes. Full article

Studies have shown that the iron concentration in the peritoneal fluid of women is associated with the severity of endometriosis. Therefore, investigation of iron metabolism-related genes (IM-RGs) in endometriosis holds significant implications for both prevention and therapeutic strategies in affected patients. Differentially expressed IM-RGs (DEIM-RGs) were identified by intersecting IM-RGs with differentially expressed genes derived from GSE86534. Mendelian randomization analysis was employed to determine DEIM-RGs causally associated with endometriosis, with subsequent verification through sensitivity analyses and the Steiger test. Biomarkers associated with IM-RGs in endometriosis were validated using expression data from GSE86534 and GSE105764. Functional annotation, regulatory network construction, and immunological profiling were conducted for these biomarkers. Single-cell RNA sequencing (scRNA-seq) (GSE213216) was utilized to identify distinctively expressed cellular subsets between endometriosis and controls. Experimental validation of biomarker expression was performed via reverse transcription–quantitative polymerase chain reaction (RT-qPCR). BMP6 and SLC48A1, biomarkers indicative of cellular BMP response, were influenced by a medicus variant mutation that inactivated PINK1 in complex I, concurrently enriched by both biomarkers. The lncRNA NEAT1 regulated BMP6 through hsa-mir-22-3p and hsa-mir-124-3p, while SLC48A1 was modulated by hsa-mir-423-5p, hsa-mir-19a-3p, and hsa-mir-19b-3p. Immune profiling revealed a negative correlation between BMP6 and monocytes, whereas SLC48A1 displayed a positive correlation with activated natural killer cells. scRNA-seq analysis identified macrophages and stromal stem cells as pivotal cellular components in endometriosis, exhibiting altered self-communication networks. RT-qPCR confirmed elevated expression of BMP6 and SLC48A1 in endometriosis samples relative to controls. Both BMP6 and SLC48A1 were consistently overexpressed in endometriosis, reinforcing their potential as biomarkers. Moreover, macrophages and stromal stem cells were delineated as key contributors. These findings provide novel insights into therapeutic and preventive approaches for patients with endometriosis. Full article

Introduction: Noggin encoding (NOG) gene plays a critical role in early embryogenesis and development of bones, joints, cartilage, eyes, and neural tissue. The NOG gene encodes the noggin protein. Noggin is the only secreted inhibitor of bone morphogenetic protein (BMP) that is associated with abnormal phenotypes in humans. The most commonly observed manifestations of NOG gene mutations include bilateral conductive hearing loss, proximal symphalangism, broad thumbs, hyperopia, and a distinct facial appearance. This genetic disorder was first reported in 1990 by Teunissen and Cremers. Since then, various phenotypic presentations of NOG mutation have been reported, leading to the introduction of the term NOG-related symphalangism spectrum disorder (NOG-SSD). Case report: In this report, we describe a family (mother and daughter) with bilateral mixed hearing loss. Both patients had hyperopia, distinct facial appearance with hemicylindrical nose, broad thumbs, and syndactyly of the second and third toes. Genetic testing confirmed a NOG gene mutation. Bilateral stapedotomy was successfully performed, resulting in significant hearing improvement. However, due to sensorineural component of hearing loss, complete hearing recovery was only achieved with the use of hearing aids. Discussion: The etiology of the sensorineural component of hearing loss in NOG-SSD remains unclear. In animal models, the NOG gene is essential for inner ear development, while in humans, only middle ear malformations have been reported. The phenotypic variability observed in individuals with NOG mutations is very wide, suggesting that the sensorineural component of hearing loss could represent one of the possible manifestations. Conclusions: Conductive hearing loss is the primary manifestation of the NOG-SSD, and all previously reported cases of NOG gene mutations have presented exclusively with conductive hearing loss. It is possible that additional genetic factors, not necessarily directly related to the NOG gene but present in this family, contribute to the development of the sensorineural component of hearing loss, although thorough genetic testing did not reveal any additional mutation. This is, to our knowledge, the first report of mixed hearing loss associated with a NOG mutation confirmed preoperatively. Further studies are needed to determine whether the sensorineural component represents a primary manifestation or arises from secondary mechanisms. Full article

Background: The bone morphogenetic protein (BMP) signaling pathway is essential for lung development. BMP4, a key regulator, binds to type I (BMPR1) and type II (BMPR2) receptors to initiate downstream signaling. While the inactivation of Bmpr1a and Bmpr1b leads to tracheoesophageal fistulae, the role of BMPR2 mutations in lung epithelial development remains unclear. Methods: We generated induced pluripotent stem cells (iPSCs) from a patient carrying a BMPR2 mutation (c.631C>T), and gene-corrected isogenic controls were created using CRISPR/Cas9. These iPSCs were differentiated into lung progenitor cells and subsequently cultured to generate alveolar and airway organoids. The differentiation efficiency and epithelial lineage specification were assessed using immunofluorescence, flow cytometry, and qRT-PCR. Results: BMPR2-mutant iPSCs showed no impairment in forming a definitive or anterior foregut endoderm. However, a significant reduction in lung progenitor cell differentiation was observed. Further, while alveolar epithelial differentiation remained largely unaffected, airway organoids derived from BMPR2-mutant cells exhibited impaired goblet and ciliated cell development, with an increase in basal and club cell markers, indicating skewing toward undifferentiated airway cell populations. Conclusions: BMPR2 dysfunction selectively impairs late-stage lung progenitor specification and disrupts airway epithelial maturation, providing new insights into the developmental impacts of BMPR2 mutations. Full article

Pediatric high-grade gliomas (pHGGs), particularly diffuse midline gliomas (DMGs), are among the most lethal brain tumors due to poor survival and resistance to therapies. DMGs possess a distinct genetic profile, primarily driven by hallmark mutations such as H3K27M, ACVR1, and PDGFRA mutations/amplifications and TP53 inactivation, all of which contribute to tumor biology and therapeutic resistance. Developing physiologically relevant preclinical models that replicate both tumor biology and the tumor microenvironment (TME) is critical for advancing effective treatments. This review highlights recent progress in in vitro, ex vivo, and in vivo models, including patient-derived brain organoids, genetically engineered mouse models (GEMMs), and region-specific midline organoids incorporating SHH, BMP, and FGF2/8/19 signaling to model pontine gliomas. Key genetic alterations can now be introduced using lipofectamine-mediated transfection, PiggyBac plasmid systems, and CRISPR-Cas9, allowing the precise study of tumor initiation, progression, and therapy resistance. These models enable the investigation of TME interactions, including immune responses, neuronal infiltration, and therapeutic vulnerabilities. Future advancements involve developing immune-competent organoids, integrating vascularized networks, and applying multi-omics platforms like single-cell RNA sequencing and spatial transcriptomics to dissect tumor heterogeneity and lineage-specific vulnerabilities. These innovative approaches aim to enhance drug screening, identify new therapeutic targets, and accelerate personalized treatments for pediatric gliomas. Full article

The transforming growth factor-beta (TGF-β) superfamily plays a crucial role in regulating female reproductive traits, particularly litter size, in small ruminants, such as sheep and goats. This review comprehensively examines the molecular mechanisms through which TGF-β superfamily members—including bone morphogenetic proteins (BMPs), growth differentiation factor 9 (GDF9), inhibin (INHA and INHB), and associated signaling genes—influence ovarian follicular development, ovulation rate, and ultimately, litter size. We synthesize recent findings on polymorphisms in key genes, such as BMPR1B, BMP15, GDF9, inhibins and SMADs family genes, across diverse sheep and goat breeds worldwide. The manuscript highlights how specific mutations in these genes create an intricate signaling network that modulates granulosa cell proliferation, follicular sensitivity to FSH, and the prevention of dominant follicle selection. These molecular interactions result in increased ovulation rates and larger litter sizes in prolific breeds. The gene dosage effects observed in heterozygous versus homozygous mutation carriers further illuminate the complex nature of these reproductive regulations. This improved the understanding of the genetic basis for prolificacy provides valuable insights for marker-assisted selection strategies aimed at enhancing reproductive efficiency in small ruminant breeding programs, with significant implications for improving livestock productivity and economic outcomes. Full article

Background: While the mechanism of asymmetric gonadal development is generally understood, the mechanism of asymmetric oviduct development remains unclear. Methods: Right and left oviducts were collected from chick embryos at three developmental stages (Embryonic day 7.5, E9.5, and E11.5) for RNA-seq analysis (RNA-seq). Whole-genome resequencing (WGRS) was performed on hens with bilateral reproductive systems (a rare natural occurrence) and unilateral controls. These data were co-analyzed with public RNA-seq data of female embryonic gonads at different developmental stages (E4.5, E5.5, and E6.5) to screen for candidate genes affecting oviduct degeneration/development. Results: RNA-seq analyses showed that a total of 27, 10, and 38 DEGs were identified between the left and right oviducts at E7.5, E9.5, and E11.5, respectively. WGRS analyses revealed 1045 differentially mutated genes (DMGs) between bilateral (D) and unilateral (S) groups. Preliminary validation highlighted BMP7, PAK3, SLC6A11, PITX2, and SMC1B as candidate genes influencing oviduct asymmetry. Conclusions: This study provides insights into the genetic basis of asymmetric oviduct development and lays the groundwork for breeding hens with bilateral reproductive systems. Full article

Type VII osteogenesis imperfecta (OI), caused by recessive CRTAP mutations, is predominantly lethal in the first year of life. Due to its early lethality, little is known about bone dysplasia mechanism. RNA-seq analysis of differentiated osteoblasts of siblings with a non-lethal homozygous CRTAP-null variant showed an enrichment of gene ontology terms involved in DNA replication and cell cycle compared to control. BrdU incorporation confirmed a ≈2-fold increase in proliferation in non-lethal proband osteoblasts in comparison to control cells. In addition, the expression of cyclin dependent kinase inhibitor 2A (CDKN2A), encoding a protein involved in cell cycle inhibition, was significantly reduced (>50%) in CRTAP-null osteoblasts, while cyclin B1 (CCNB1), encoding a promoter of the cell cycle, was enhanced. Ossification and bone and cartilage development gene ontology pathways were enriched among upregulated genes throughout osteoblast differentiation, as was protein secretion. Ingenuity pathway analysis indicated an upregulation of BMP2 signaling, supported by increase in both BMP2 and MSX2, an early BMP2-responsive gene, by qPCR. Throughout differentiation, CRTAP-null osteoblasts showed a decrease in transcripts related to cell adhesion and extracellular matrix organization pathways. We propose that increased proliferation and osteogenesis of type VII OI osteoblasts may be stimulated through upregulation of BMP2 signaling, altering bone homeostasis, and leading to weaker bones. Full article

Reproductive performance in sheep plays a crucial role in determining the economic efficiency of the industry, with increasing litter size being a key focus for genetic improvement. The BMP15 gene is widely recognized as a major gene influencing sheep fertility. In this study, specific mutations in the BMP15 gene of Gobi short tail sheep were identified through direct sequencing, and these mutations were genotyped using the MassARRAY system. The g.54285159_54285161TTA indel was significantly associated with litter size in Gobi short tail sheep (p < 0.05). Three mutations, including g.54291460G>A, g.54288671C>T, and the g.54285159_54285161TTA indel, were significantly associated with litter size in Ujimqin sheep (p < 0.05). Furthermore, the promoter activity analysis demonstrated that the A allele exhibited significantly higher promoter activity compared to the G allele of the g.54291460G>A mutation. These findings highlight valuable genetic markers for improving sheep litter size and provide a robust theoretical foundation for further research on the BMP15 gene’s role in reproduction. Full article

Congenital spinal deformities (CSDs) are rare but severe conditions caused by abnormalities in vertebral development during embryogenesis. These deformities, including scoliosis, kyphosis, and lordosis, significantly impair patients’ quality of life and present challenges in diagnosis and treatment. This review integrates genetic, molecular, and developmental insights to provide a comprehensive framework for classifying and understanding CSDs. Traditional classification systems based on morphological criteria, such as failures in vertebral formation, segmentation, or mixed defects, are evaluated alongside newer molecular-genetic approaches. Advances in genetic technologies, including whole-exome sequencing, have identified critical genes and pathways involved in somitogenesis and sclerotome differentiation, such as TBX6, DLL3, and PAX1, as well as key signaling pathways like Wnt, Notch, Hedgehog, BMP, and TGF-β. These pathways regulate vertebral development, and their disruption leads to skeletal abnormalities. The review highlights the potential of molecular classifications based on genetic mutations and developmental stage-specific defects to enhance diagnostic precision and therapeutic strategies. Early diagnosis using non-invasive prenatal testing (NIPT) and emerging tools like CRISPR-Cas9 gene editing offer promising but ethically complex avenues for intervention. Limitations in current classifications and the need for further research into epigenetic and environmental factors are discussed. This study underscores the importance of integrating molecular genetics into clinical practice to improve outcomes for patients with CSDs. Full article

(1) Background: Litter size is one of the most important economic traits of sheep. The FecB locus has been extensively studied due to its significant impact on litter size in Hu sheep, and BMP15 and GDF9 have also been reported as major genes associated with litter size in sheep. This study aimed to identify variants of BMP15 and GDF9 and perform an association analysis of these variants with litter size in the Hu sheep breed. (2) Methods: In this study, exons of the BMP15 and GDF9 genes were fully sequenced to identify polymorphisms in Hu sheep. Population genetic parameters and haplotype frequencies were estimated, and an association analysis between these polymorphic loci and litter size was performed. Additionally, the protein structures of the wild-type and mutated BMP15 and GDF9 genes were predicted. (3) Results: The polymorphisms of the BMP15 and GDF9 genes were investigated within their exon regions, revealing mutations at four previously reported sites: BMP15 c.31_33CTTdel and GDF9 (G2, G3, and G4) in Hu sheep, with no novel variants were detected. Genetic analysis indicated that the GDF9-G3 and GDF9-G4 loci have low polymorphisms, whereas the BMP15 c.31_33CTTdel and the GDF9-G2 locus are moderately polymorphic. The mutation sites in the BMP15 and GDF9 genes were under Hardy–Weinberg equilibrium. Association analysis revealed that the BMP15 c.31_33CTTdel and GDF9 (G2, G3, and G4) mutations are not associated with litter size in Hu sheep. Protein structure prediction indicated that the mutations in BMP15 and GDF9 resulted in alterations to their tertiary structures. (4) Conclusions: In this study, four reported mutations in the BMP15 and GDF9 genes can also be detected in the Hu sheep breed. In these mutations, the G2 and G3 mutations of GDF9 did not alter the amino acid sequence, while the BMP15 c.31_33CTTdel mutation and the GDF9 G4 mutation resulted in protein structure alteration. Furthermore, the BMP15 c.31_33CTTdel mutation and the GDF9 mutations (G2, G3, G4) were associated with an increased tendency in litter size. However, no significant difference was observed (p > 0.05). This study provides valuable insights for improving the lambing performance of Hu sheep. Full article