Bone Morphogenetic Protein Signaling Research Articles

Nlnemo suppresses of BMP signaling in wing development of the brown planthopper, Nilaparvata lugens.

Nemo-like kinases (NLKs) integrate multiple signaling pathways and exhibit functional diversity in developmental processes, including the bone morphogenetic protein (BMP) pathway. However, their roles in insect wing development, particularly in hemimetabolous insects like the brown planthopper (Nilaparvata lugens), remain poorly understood. Here, we investigated the role of Nlnemo (Nlnmo), an NLK, in the wing development of N. lugens. We cloned and characterized Nlnmo and found it highly conserved across insect species. Expression analysis revealed higher Nlnmo levels in brachypterous compared to macropterous strains, particularly in wing buds. RNA interference (RNAi) of Nlnmo led to enlarged wing and thickened veins, indicating its inhibitory role in wing development. Further analysis revealed that Nlnmo suppresses BMP signaling by downregulating Nlmad1 and Nldpp. Dual knockdown of Nlmad1 and Nlnmo demonstrated that Nlnmo mitigates Nlmad1-mediated effects on wing development. These findings establish Nlnmo function as a key suppressor of wing development in N. lugens via BMP signaling inhibition through Nlmad1. This study deepens our understanding of the molecular mechanisms underlying wing development in in N. lugens and highlights potential pest management strategies by targeting migration-related traits.

The zinc-finger protein POGZ associates with Polycomb repressive complex 1 to regulate bone morphogenetic protein signaling during neuronal differentiation.

Polycomb Repressive Complex 1 (PRC1) is a family of epigenetic regulators critical for mammalian development. Elucidating PRC1 composition and function across cell types and developmental stages is key to understanding the epigenetic regulation of cell fate determination. In this study, we discovered POGZ, a prominent Autism Spectrum Disorder (ASD) risk factor, as a novel component of PRC1.6, forming the PRC1.6-POGZ complex. Functional assays revealed that POGZ elicits transcriptional repression that is dependent on RING1B expression. Analysis of publicly available ChIP-Seq data showed that POGZ highly colocalizes with RING1B and HP1γ, two PRC1.6 components, at genes involved in multiple aspects of transcriptional regulation in the embryonic mouse cortex. Although Pogz knockout (KO) does not compromise stem cell pluripotency, Pogz ablation in neuronal progenitor cells (NPCs) led to widespread transcriptomic dysregulation with failed activation of key neuronal genes. Finally, we demonstrated that PRC1.6-POGZ regulates neuronal differentiation by repressing the bone morphogenetic protein (BMP) signaling pathway. These findings reveal a mechanism by which PRC1 and POGZ coordinate transcriptional regulation during neuronal differentiation, which offers insights into how disruptions in this pathway may contribute to neurodevelopmental disorders such as ASD.

Divergent endothelial mechanisms drive arteriovenous malformations in Alk1 and SMAD4 loss-of-function.

Hereditary hemorrhagic telangiectasia is an autosomal dominant disorder caused by mutations in the bone morphogenetic protein signaling pathway, leading to arteriovenous malformations. While previously thought to share molecular and cellular dysregulation, this study reveals highly distinct mechanisms depending on whether mutations occur in Alk1 or SMAD4. Loss of SMAD4 enhances endothelial cell responses to flow, including flow-regulated transcription and cell migration against blood flow, causing excessive pruning of capillaries and the formation of single large shunts. Conversely, Alk1 deficiency disrupts endothelial flow responses, including cell polarization and directional migration, leading to a dense vascular network and the persistence of a malformation nidus. In vivo cell population tracking of mutant cells validates unique endothelial cell migration defects. Mosaic cell culture models further illustrate that mutant cells co-opt wild-type cells driving distinct Alk1 or SMAD4 mutant-like behavioral defects. These findings demonstrate that arteriovenous malformations develop through fundamentally different cellular mechanisms based on the specific genetic mutation emphasizing the need for tailored diagnostic and therapeutic strategies.

Disruption of BMP and FGF signaling prior to blastema formation causes permanent bending and skeletal malformations in Poecilia latipinna tail fin.

Teleost fish, such as Poecilia latipinna, exhibit remarkable regenerative capabilities, making them excellent models for studying tissue regrowth. They regenerate body parts like the tail fin through epimorphic regeneration, involving wound healing, blastema formation (a pool of proliferative cells), and tissue differentiation. Bone Morphogenetic Protein (BMP) and Fibroblast Growth Factor (FGF) signaling pathways play crucial roles in this process, but their specific functions during blastema formation remain unclear. To explore this, BMP and FGF signaling were inhibited using targeted drug treatments prior to blastema formation in amputated tail fins. The treatment group of P. latipinna received drugs at set intervals, and analyses were conducted using skeletal staining, gene expression via quantitative real-time PCR, and protein analysis with Western blotting to assess blastema formation, extracellular matrix (ECM) remodeling, and skeletal patterning. Dual inhibition of BMP and FGF pathways led to significant regenerative defects, including bent blastema and disrupted bone structure, along with downregulation of essential patterning genes like sonic hedgehog (Shh) and bmp2b. Additionally, ECM remodeling and epithelial-to-mesenchymal transition (EMT) were impaired, as shown by reduced matrix metalloproteinases (MMP2 and MMP9), hindering cell migration and blastema stability. Cell proliferation was markedly decreased, as evidenced by reduced proliferating cell nuclear antigen (PCNA) expression and bromodeoxyuridine (BrdU) incorporation, while apoptosis increased, with elevated markers like caspase 3 (casp3) and higher DNA fragmentation. These findings indicate that BMP and FGF signaling are essential for blastema formation and skeletal patterning, with their inhibition causing major regenerative abnormalities.

Therapeutic potential of targeting BMP/ALK pathway in pathological retinal neovascularization

Aims/Purpose: Pathological retinal neovascularization (PRNV) in ischemic retinopathies presents a significant clinical challenge. This study investigates the role of bone morphogenetic protein (BMP) signaling via ALK receptors in PRNV, with a focus on epigenetic modifications.Methods: The oxygen‐induced retinopathy (OIR) mouse model was utilized to investigate BMP signaling. Experimental groups included OIR mice treated with Noggin (a BMP inhibitor) or vehicle via ip from postnatal day 12‐16. Additional groups included a combined ALK2 and ALK3 endothelial conditional knockout mice (ALK2/3eKO), subjected to OIR. Capillary degeneration and neovascularization were assessed at postnatal day 17 in flat‐mount retinas using isolectin‐B4 staining. Immunostaining of retinal sections evaluated BMP2, BMP4, and ALK3 localization. In vitro experiments involved human retinal endothelial cells (HRECs) treated with BMP2 (50 ng/ml) or exposed to hypoxia (1% O2) for 48 hours. The impact of BMP2 on vascular endothelial growth factor (VEGF) was assessed through ELISA. MicroRNA (miRNA) expression was analyzed using the GeneChip miRNA 3.0 array. DNA methylation of HRECs was quantified using a colorimetric kit.Results: Immunostaining revealed an upregulation of BMP2, BMP4, and ALK3 expression in retinal vessels. Noggin‐treated and ALK2/3eKO OIR mice exhibited a significant reduction in capillary dropout and neovascularization (p < 0.01). BMP2 treatment of HRECs elevated VEGF production. MiRNA array analysis indicated significant alterations by BMP2 (4%) and hypoxia (5%), including miRNAs linked to VEGF signaling and angiogenesis. Specifically, BMP2 downregulated miR‐4521, miR‐769‐3p, miR‐23b‐5p, miR‐3195, and miR‐6781‐5p, while upregulating miR‐126‐3p, miR‐921, miR‐7515, miR‐29c, and miR‐20b‐5p. Interestingly, BMP2 and hypoxia induced similar effects on certain miRNAs, such as miR‐769‐3p, miR‐23b, and miR‐20b. The DNA methylation assay demonstrated a statistically significant reduction induced by BMP2.Conclusions: BMP/ALK signaling plays a potential role in the pathogenesis of PRNV, possibly mediated through epigenetic modifications. Thereby, targeting BMP/ALK signaling holds a promise to mitigate PRNV in ischemic retinopathies

The modulatory role of bone morphogenetic protein signaling in cerebellar synaptic plasticity.

Bone morphogenetic proteins (BMPs), regulators of bone formation, have been implicated in embryogenesis and morphogenesis of various tissues and organs. BMP signaling plays a role in the formation of appropriate synaptic connections and development of normal neural circuits in the brain. However, physiological roles of BMP signaling in postnatal neural functions, including synaptic plasticity, remain largely unknown. Long-term depression (LTD) of synaptic transmission at parallel fiber (PF)-Purkinje cell (PC) synapses in the cerebellum has been suggested one neuronal mechanism underlying cerebellar functions. Here, we explored the contribution of BMP signaling to the induction of mouse cerebellar LTD. We first demonstrated that BMP2 and/or 4 were expressed in GABAergic neurons in mature networks of the cerebellar cortex. mRNA encoding BMP receptor type 1B (Bmpr1b) was expressed in the PC layer. Exogenous application of noggin, a BMP ligand inhibitor, suppressed the induction of cerebellar LTD by conjunctive stimulation, which caused normal LTD under control condition. Furthermore, mice deficient in BMPR1B exhibited attenuation of the extent of LTD induction, whereas they showed normal excitatory synaptic transmission at PF-PC synapses. These results suggest that after postnatal development, BMP signaling activated by BMPR1B, expressed in the PC layer, plays a crucial role in the facilitation of cerebellar LTD, leading to the modulation of cerebellar functions and behaviors.

Alk1/Endoglin signaling restricts vein cell size increases in response to hemodynamic cues

Hemodynamic cues are thought to control blood vessel hierarchy through a shear stress set point, where flow increases lead to blood vessel diameter expansion, while decreases in blood flow cause blood vessel narrowing. Aberrations in blood vessel diameter control can cause congenital arteriovenous malformations (AVMs). We show in zebrafish embryos that while arteries behave according to the shear stress set point model, veins do not. This behavior is dependent on distinct arterial and venous endothelial cell (EC) shapes and sizes. We show that arterial ECs enlarge more strongly when experiencing higher flow, as compared to vein cells. Through the generation of chimeric embryos, we discover that this behavior of vein cells depends on the bone morphogenetic protein (BMP) pathway components Endoglin and Alk1. Endoglin (eng) or alk1 (acvrl1) mutant vein cells enlarge when in normal hemodynamic environments, while we do not observe a phenotype in either acvrl1 or eng mutant ECs in arteries. We further show that an increase in vein diameters initiates AVMs in eng mutants, secondarily leading to higher flow to arteries. These enlarge in response to higher flow through increasing arterial EC sizes, fueling the AVM. This study thus reveals a mechanism through which BMP signaling limits vein EC size increases in response to flow and provides a framework for our understanding of how a small number of mutant vein cells via flow-mediated secondary effects on wildtype arterial ECs can precipitate larger AVMs in disease conditions, such as hereditary hemorrhagic telangiectasia (HHT).

Inhibition of Bone Morphogenetic Protein Signaling Prevents Tau Pathology in iPSC Derived Neurons and PS19 Mice.

Many neurodegenerative disorders share a common pathologic feature involving the deposition of abnormal tau protein in the brain (tauopathies). This suggests that there may be some shared pathophysiologic mechanism(s). The largest risk factor for the majority of these disorders is aging, suggesting involvement of the aging process in the shared pathophysiology. We test the hypothesis that an increase in bone morphogenetic protein (BMP) signaling that occurs during aging contributes to the onset and progression of tauopathies. Human induced pluripotent stem cell (iPSC)-derived neurons from patients with Alzheimer's disease (AD) were used to investigate the effects of BMP signaling on tau phosphorylation and release and the mechanisms underlying these effects. Wildtype mice were used to examine effects of BMP signaling in vivo. P301S (PS19) mice were examined for the effects of BMP signaling in a model of tauopathy. Here, we show that BMP signaling, mediated by non-canonical p38 signaling, increases tau phosphorylation and release of p-tau in human iPSC-derived AD neurons. Further, there is an interaction between BMP signaling and apolipoprotein E4 (ApoE4) that significantly increases tau phosphorylation and release compared with ApoE3 neurons. Inhibiting BMP signaling reduces the changes in tau in the cultured human neurons, and it limits tau pathology and prevents cognitive decline in PS19 mice. Our study suggests that the age-related increase in BMP signaling may participate in the onset and progression of tau pathology. Thus, therapeutic interventions that reduce BMP signaling in the aging brain could potentially slow or prevent development of diseases involving tau hyperphosphorylation. ANN NEUROL 2024.

The C. elegans LON-1 protein requires its CAP domain for function in regulating body size and BMP signaling.

The CAP (Cysteine-rich secretory proteins, Antigen-5, Pathogenesis-Related) proteins are widely expressed and have been implicated to play diverse roles ranging from mammalian reproduction to plant immune response. Increasing evidence supports a role of CAP proteins in lipid binding. The C. elegans CAP protein LON-1 is known to regulate body size and Bone Morphogenetic Protein (BMP) signaling. LON-1 is a secreted protein with a conserved CAP domain and a C-terminal unstructured domain with no homology to other proteins. In this study, we report that the C-Terminal Domain (CTD) of LON-1 is dispensable for its function. Instead, key conserved residues located in the CAP domain are critical for LON-1 function in vivo. We further showed that LON-1 is capable of binding sterol, but not fatty acid, in vitro, and that certain key residues implicated in LON-1 function in vivo are also important for LON-1 sterol binding in vitro. These findings suggest a role of LON-1 in regulating body size and BMP signaling via sterol binding.

Mechanism of traditional Chinese medicine in treating vascular calcification in chronic kidney disease based on BMP and SIRT signaling pathways

Vascular calcification significantly increases the incidence of cardiovascular disease and all-cause mortality patients with chronic kidney disease(CKD), severely affecting their health and lifespan. However, the mechanisms underlying vascular calcification in CKD remain incompletely understood, and the available therapeutic agents are limited. Research has found that the transformation of vascular smooth muscle cells(VSMCs) from a contractile phenotype to an osteoblast-like phenotype is a key step in CKD-related vascular calcification. As research on the pathogenesis of calcification progresses, it has been demonstrated that bone morphogenetic protein(BMP) and silent information regulator(SIRT) signaling pathways can participate in the process of vascular calcification by regulating the osteogenic transdifferentiation of VSMCs. Traditional Chinese medicine(TCM) has accumulated a wealth of valuable experience in the prevention and treatment of kidney diseases over centuries. Modern research indicates that TCM, with its multi-pathway, multi-target, and low-toxicity properties, has shown certain advantages in the prevention and treatment of CKD-related vascular calcification and in improving patients' quality of life. Therefore, in this study, we will introduce the latest research progress of TCM in preventing and treating CKD-related vascular calcification, particularly focusing on the BMP and SIRT signaling pathways, with the aim of providing ideas for the clinical diagnosis and treatment of CKD-related vascular calcification with TCM and related basic research.

A Chemically Defined Culture for Tooth Reconstitution.

It is known for decades that dental epithelium and mesenchyme can reconstitute and regenerate a functional tooth. However, the mechanism of tooth reconstitution remains largely unknown due to the lack of an efficient in vitro model. Here, a chemically defined culture system is established that supports tooth reconstitution, further development with normal anatomy, and prompt response to chemical interference in key developmental signaling pathways, termed as toothoids. By using such a system, it is discovered that, during reconstitution, instead of resetting the developmental clock, dental cells reorganized and restarted from the respective developmental stage where they are originally isolated. Moreover, co-stimulation of Activin A and Hedgehog/Smoothened agonist (SAG) sustained the initial induction of tooth fate from the first branchial arch, which would be otherwise quickly lost in culture. Furthermore, activation of Bone Morphogenetic Protein (BMP) signaling triggered efficient enamel formation in the late-stage toothoids, without affecting the normal development of ameloblasts. Together, these data highlight the toothoid culture as a powerful tool to dissect the molecular mechanisms of tooth reconstitution and regeneration.

Investigating the Role of Primary Cilia and Bone Morphogenetic Protein Signaling in Periodontal Ligament Response to Orthodontic Strain In Vivo and In Vitro: A Pilot Study.

Periodontal ligament (PDL) cells are crucial for mechanosensation and mechanotransduction within the PDL, yet the role of primary cilia in orthodontic force transmission has not been examined. While bone morphogenetic protein (BMP) signaling significantly influences ciliary function, its effect on cellular responses to mechanical stress has not been investigated. This study aims to investigate whether primary cilia and BMP signaling are involved in the periodontal ligament's response to orthodontic tooth movement and the resultant mechanical strain. To visualize primary cilia, human PDL cells were cultured on glass-bottom dishes for five days, with a subset fixed daily, followed by immunostaining with anti-acetylated α-tubulin and Alexa Fluor 568 and imaging using a fluorescence microscope under 405 nm and 561 nm laser excitation. Human PDL cells were grown on Bioflex® culture plates and subsequently exposed to static tensile strains of 2.5%, 5%, 10%, 20%, on a FX-6000T™ Tension System for 24 h. RT-qPCR was performed to evaluate changes in expression of primary cilia via Ift88 expression, mechanotransduction via Cox2 expression, and BMP signaling-related genes. Histological specimens from orthodontically loaded and control human premolars were investigated for primary cilia and BMP signaling using immunohistochemistry and confocal microscopy. Primary cilia were observed in PDL cells from day one, with their incidence and length increasing over time alongside cell density. BMP signaling components, including upregulated genes such as Bmp7 (10.99-14.97 fold), Alk2 (3.19-5.45 fold), and Bmpr2 (1.64-8.40 fold), consistently responded to strain, while Cox2 and Ift88 showed differential regulation depending on strain intensity. In vivo, orthodontic movement activated BMP signaling and increased primary cilium incidence in the PDL. These findings indicate the potential role of primary cilia and BMP signaling in the mechanosensitivity of PDL cells under orthodontic forces. Further studies are required to understand the complex mechanotransduction mechanisms and role of these components in cellular adaptation during orthodontic tooth movement.

Bone morphogenetic protein signaling pathway– Ethanol interactions disrupt palate formation independent of gata3

Fetal Alcohol Spectrum Disorders (FASD) describes a wide array of neurological defects and craniofacial malformations, associated with ethanol teratogenicity. While there is growing evidence for a genetic component to FASD, little is known of the genes underlying these ethanol-induced defects. Along with timing and dosage, genetic predispositions may help explain the variability within FASD. From a screen for gene-ethanol interactions, we found that mutants for Bmp signaling components are ethanol-sensitive leading to defects in the zebrafish palate. Loss of Bmp signaling results in reductions in gata3 expression in the maxillary domain of the neural crest in the 1st pharyngeal arch, leading to palate defects while upregulation of human GATA3 rescues these defects. Here, we show that ethanol-treated Bmp mutants exhibit misshaped and/or broken trabeculae. Surprisingly, up regulation of GATA3 does not rescue ethanol-induced palate defects and gata3 expression was not altered in ethanol-treated Bmp mutants or dorsomorphin-treated larvae. Timing of ethanol sensitivity shows that Bmp mutants are ethanol sensitive from 10 to 18 hours post-fertilization (hpf), prior to Bmp’s regulation of gata3 in palate formation. This is consistent with our previous work with dorsomorphin-dependent knock down of Bmp signaling from 10 to 18 hpf disrupting endoderm formation and subsequent jaw development. Overall, this suggests that ethanol disrupts Bmp-dependent palate development independent of and earlier than the role of gata3 in palate formation by disrupting epithelial development. Ultimately, these data demonstrate that zebrafish is a useful model to identify and characterize gene-ethanol interactions and this work will directly inform our understanding of FASD.

Methyl-Beta-Cyclodextrin Restores Aberrant Bone Morphogenetic Protein 2-Signaling in Bone Marrow Stromal Cells Obtained from Aged C57BL/6 Mice.

During aging, disruptions in various signaling pathways become more common. Some older patients will exhibit irregular bone morphogenetic protein (BMP) signaling, which can lead to osteoporosis (OP)-a debilitating bone disease resulting from an imbalance between osteoblasts and osteoclasts. In 2002, the Food and Drug Administration (FDA) approved recombinant human BMP-2 (rhBMP-2) for use in spinal fusion surgeries as it is required for bone formation. However, complications with rhBMP-2 arose and primary osteoblasts from OP patients often fail to respond to BMP-2. Although patient samples are available for study, previous medical histories can impact results. Consequently, the C57BL/6 mouse line serves as a valuable model for studying OP and aging. We find that BMP receptor type Ia (BMPRIa) is upregulated in the bone marrow stromal cells (BMSCs) of 15-month-old mice, consistent with prior data. Furthermore, conjugating BMP-2 with Quantum Dots (QDot®s) allows effective binding to BMPRIa, creating a fluorescent tag for BMP-2. Furthermore, after treating BMSCs with methyl-β-cyclodextrin (MβCD), a disruptor of cellular endocytosis, BMP signaling is restored in 15-month-old mice, as shown by von Kossa assays. MβCD has the potential to restore BMPRIa function, and the BMP signaling pathway offers a promising avenue for future OP therapies.

Bone Morphogenetic Protein signaling pathway - ethanol interactions disrupt palate formation independent of gata3.

Bmp pathway mutants are ethanol sensitive resulting in palate defects. Ethanol disrupts Bmp-dependent palate development independent of gata3 . Timing of ethanol sensitivity suggests ethanol disrupts Bmp-dependent epithelial morphogenesis.

Bone morphogenetic protein 4 induces hematopoietic stem cell development from murine hemogenic endothelial cells in culture

Hematopoietic stem cells (HSCs) develop from hemogenic endothelial cells (HECs) during mouse embryogenesis. Understanding the signaling molecules required for HSC development is crucial for the invitro derivation of HSCs. We previously induced HSCs from embryonic HECs, isolated at embryonic day 10.5 (E10.5), in serum-free culture conditions with stem cell factor, thrombopoietin, and an endothelial feeder layer. Here, we aimed to elucidate signal requirements for inducing HSCs from earlier-stage HECs. Single-cell RNA sequencing (RNA-seq) analysis detected bone morphogenetic protein (BMP) signaling activation in E9.5 HECs. Adding BMP4 to the culture conditions led to the induction of HSCs from E9.5 HECs. Furthermore, isolating BMP4 receptor-expressing HECs from E9.5 embryos enriched progenitors with HSC-forming ability. This study identified BMP4 as an essential factor promoting the differentiation of early HECs into HSCs, opening up new possibilities for the invitro derivation of HSCs.

Hepatoprotective and neuroprotective effects of quinacrine against bile duct ligation-induced hepatic encephalopathy in rats: Role of bone morphogenetic proteins signaling

AimsThis study aimed to assess the potential protective effect of quinacrine, an FDA approved antimalarial drug with reported anti-inflammatory effects, on hepatic encephalopathy (HE) in a bile duct ligation (BDL) experimental model and to investigate the mechanisms responsible for this effect, namely those associated with the liver-brain axis, particularly, bone morphogenetic protein 2 (BMP2) signaling. Materials and methodsFive groups of rats were selected at random: sham, BDL, (BDL+ quinacrine 5), (BDL+ quinacrine 10), and (quinacrine 10 + sham). Daily Intraperitoneal (I.P.) administration of quinacrine was initiated on the surgery day and continued for 28 days. Key findingsResults showed that rats that underwent BDL exhibited marked elevation of serum liver enzymes, ammonia, total bilirubin, together with oxidative stress, inflammation, dysregulated farnesoid x receptor (FXR), dysregulated BMP2 signaling and escalated fibrotic markers indicating hepatotoxicity, cholestasis and fibrosis. Besides, neurotoxicity was detected as manifested by cognitive deficits and dysregulation of hippocampal FXR, BMP2 signaling, WNT3A signaling, brain derived neurotrophic factor (BDNF), phospholipase A2 (PLA2) and glial fibrillary acidic protein (GFAP). In contrast, co-treatment with quinacrine mitigated BDL-induced hepatotoxicity, cholestasis, fibrosis, and neurotoxicity. Notably, quinacrine improved learning and memory and restored FXR, BMP2 signaling in the liver and hippocampus. In addition, quinacrine restored hippocampal WNT3A signaling, BDNF, whereas it downregulated expression of hippocampal PLA2 and GFAP. SignificanceThese findings demonstrated implication of BMP2 signaling in the molecular process of BDL-induced HE and proposed that quinacrine has potential hepatoprotective and neuroprotective properties against HE.

Depolarization induces calcium-dependent BMP4 release from mouse embryonic palate mesenchymal cells

Bone Morphogenetic Protein (BMP) signaling is essential for craniofacial development, though little is known about the mechanisms that govern BMP secretion. We show that depolarization induces calcium-dependent BMP4 release from mouse embryonic palate mesenchyme. We show endogenous transient changes in intracellular calcium occur in cranial neural crest cells, the cells from which embryonic palate mesenchyme derives. Waves of transient changes in intracellular calcium suggest that these cells are electrically coupled and may temporally coordinate BMP release. These transient changes in intracellular calcium persist in palate mesenchyme cells from embryonic day 9.5 to 13.5 mice. Disruption of a potassium channel called Kcnj2 significantly decreases the amplitude of calcium transients and the ability of cells to secrete BMP. Kcnj2 knockout mice have cleft palate and reduced BMP signaling. Our data suggest that temporal control of developmental cues is regulated by ion channels, depolarization, and intracellular calcium for mammalian craniofacial morphogenesis.

Enhanced BMP Signaling Alters Human β-Cell Identity and Function.

Inflammation contributes to the pathophysiology of diabetes. Identifying signaling pathways involved in pancreatic β-cell failure and identity loss can give insight into novel potential treatment strategies to prevent the loss of functional β-cell mass in diabetes. It is reported earlier that the immunosuppressive drug tacrolimus has a detrimental effect on human β-cell identity and function by activating bone morphogenetic protein (BMP) signaling. Here it is hypothesized that enhanced BMP signaling plays a role in inflammation-induced β-cell failure. Single-cell transcriptomics analyses of primary human islets reveal that IL-1β+IFNγ and IFNα treatment activated BMP signaling in β-cells. These findings are validated by qPCR. Furthermore, enhanced BMP signaling with recombinant BMP2 or 4 triggers a reduced expression of key β-cell maturity genes, associated with increased ER stress, and impaired β-cell function. Altogether, these results indicate that inflammation-activated BMP signaling is detrimental to pancreatic β-cells and that BMP-signaling can be a target to preserve β-cell identity and function in a pro-inflammatory environment.

Upregulation of ACSL, ND75, Vha26 and sesB genes by antiepileptic drugs resulted in genotoxicity in drosophila.

Clobazam (CLB) and Vigabatrin (VGB) are commonly used antiepileptic drugs (AEDs) in the treatment of epilepsy. Here, we have examined the genotoxic effect of these AEDs in Drosophila melanogaster. The Drosophila larvae were exposed to different concentrations of CLB and VGB containing food media. The assessment encompassed oxidative stress, DNA damage, protein levels, and gene expression profiles. In the CLB-treated group, a reduction in reactive oxygen species (ROS) and lipid peroxidation (LPO) levels was observed, alongside increased levels of superoxide dismutase (SOD), catalase (CAT), and nitric oxide (NO). Conversely, the VGB-treated group displayed contrasting results, with increased ROS and LPO and decreased SOD, CAT, and NO levels. However, both CLB and VGB induced DNA damage in Drosophila. Proteomic analysis (SDS-PAGE and OHRLCMS) in the CLB and VGB groups identified numerous proteins, including Acyl-CoA synthetase long-chain, NADH-ubiquinone oxidoreductase 75kDa subunit, V-type proton ATPase subunit E, ADP/ATP carrier protein, malic enzyme, and DNA-binding protein modulo. These proteins were found to be associated with pathways like growth promotion, notch signaling, Wnt signaling, neuromuscular junction (NMJ) signaling, bone morphogenetic protein (BMP) signaling, and other GABAergic mechanisms. Furthermore, mRNA levels of ACSL, ND75, Vha26, sesB, and Men genes were upregulated in both CLB and VGB-treated groups. These findings suggest that CLB and VGB could have the potential to induce genotoxicity and post-transcriptional modifications in humans, highlighting the importance of monitoring their effects when used as AEDs.