CCR9+CD4+ T cells are associated with disease activity in patients with rheumatoid arthritis.

An increase in CD4+ T cells in the synovium is closely linked to the pathogenesis of rheumatoid arthritis (RA). We aimed to identify the possible causes of the elevated CD4+ T cell levels and to explore the factors influencing disease activity in RA. Fifty-five RA patients, including 28 with active RA (ARA), 27 with inactive RA, and 22 healthy controls, were recruited for this study. The proportion of CCR9+CD4+ T cells and the expression of chemokine receptor 9 (CCR9) on CD4+ T cells were analyzed by flow cytometry. Enzyme-linked immunosorbent assay and chemiluminescent immunoassay were used to evaluate interleukin (IL)-17A and IL-6 levels, respectively. The proportion of CCR9+CD4+ T cells and the expression of CCR9 on CD4+ T cells increased significantly in peripheral blood (PB) and synovial fluid (SF) in ARA compared to those in inactive RA. Furthermore, SF contained more CCR9+CD4+ T cells, IL-6, and IL-17A than PB in RA patients. Moreover, CD4+ T cells in the PB of patients with RA, especially ARA, expressed more CCR9 and secreted more IL-6 and IL-17A after activation. Here, we also demonstrated that both the percentage of CCR9+ cells in CD4+ T cells and the expression of CCR9 on circulating CD4+ T cells were positively correlated with erythrocyte sedimentation rate, hypersensitive C-reactive protein, rheumatoid factor, and anti-cyclic citrullinated peptide antibody. CCR9+CD4+ T cells are elevated in PB and SF, and are associated with disease activity in patients with RA.

Echocardiographic assessment of Xenopus tropicalis heart regeneration.

BACKGROUND: Recently, it was reported that the adult X. tropicalis heart can regenerate in a nearly scar-free manner after injury via apical resection. Thus, a cardiac regeneration model in adult X. tropicalis provides a powerful tool for recapitulating a perfect regeneration phenomenon, elucidating the underlying molecular mechanisms of cardiac regeneration in an adult heart, and developing an interventional strategy for the improvement in the regeneration of an adult heart, which may be more applicable in mammals than in species with a lower degree of evolution. However, a noninvasive and rapid real-time method that can observe and measure the long-term dynamic change in the regenerated heart in living organisms to monitor and assess the regeneration and repair status in this model has not yet been established. RESULTS: In the present study, the methodology of echocardiographic assessment to characterize the morphology, anatomic structure and cardiac function of injured X. tropicalis hearts established by apex resection was established. The findings of this study demonstrated for the first time that small animal echocardiographic analysis can be used to assess the regeneration of X. tropicalis damaged heart in a scar-free perfect regeneration or nonperfect regeneration with adhesion manner via recovery of morphology and cardiac function. CONCLUSIONS: Small animal echocardiography is a reliable, noninvasive and rapid real-time method for observing and assessing the long-term dynamic changes in the regeneration of injured X. tropicalis hearts.

Ablation of cardiomyocyte-derived BDNF during development causes myocardial degeneration and heart failure in the adult mouse heart.

Objective: Brain-derived neurotrophic factor (BDNF) and its receptor TrkB-T1 were recently found to be expressed in cardiomyocytes. However, the functional role of cardiomyocyte-derived BDNF in heart pathophysiology is not yet fully known. Recent studies revealed that BDNF-TrkB pathway plays a critical role to maintain integrity of cardiac structure and function, cardiac pathology and regeneration of myocardial infarction (MI). Therefore, the BDNF-TrkB pathway may be a novel target for myocardial pathophysiology in the adult heart. Approach and results: In the present study, we established a cardiomyocyte-derived BDNF conditional knockout mouse in which BDNF expression in developing cardiomyocytes is ablated under the control of the Myosin heavy chain 6 (MYH6) promoter. The results of the present study show that ablation of cardiomyocyte-derived BDNF during development does not impair survival, growth or reproduction; however, in the young adult heart, it causes cardiomyocyte death, degeneration of the myocardium, cardiomyocyte hypertrophy, left atrial appendage thrombosis, decreased cardiac function, increased cardiac inflammation and ROS activity, and metabolic disorders, leading to heart failure (HF) in the adult heart and eventually resulting in a decrease in the one-year survival rate. In addition, ablation of cardiomyocyte-derived BDNF during the developmental stage leads to exacerbation of cardiac dysfunction and poor regeneration after MI in adult hearts. Conclusion: Cardiomyocyte-derived BDNF is irreplaceable for maintaining the integrity of cardiac structure and function in the adult heart and regeneration after MI. Therefore, the BDNF-TrkB pathway will be a novel target for myocardial pathophysiology in the adult heart.

miR-486 improves fibrotic activity in myocardial infarction by targeting SRSF3/p21-Mediated cardiac myofibroblast senescence.

The regulation of fibrotic activities is key to improving pathological remodelling post-myocardial infarction (MI). Currently, in the clinic, safe and curative therapies for cardiac fibrosis and improvement of the pathological fibrotic environment, scar formation and pathological remodelling post-MI are lacking. Previous studies have shown that miR-486 is involved in the regulation of fibrosis. However, it is still unclear how miR-486 functions in post-MI regeneration. Here, we first demonstrated that miR-486 targeting SRSF3/p21 mediates the senescence of cardiac myofibroblasts to improve their fibrotic activity, which benefits the regeneration of MI by limiting scar size and post-MI remodelling. miR-486-targeted silencing has high potential as a novel target to improve fibrotic activity, cardiac fibrosis and pathological remodelling.

Identification of cGAS as an innate immune sensor of extracellular bacterium Pseudomonas aeruginosa.

Cyclic GMP-AMP synthase (cGAS) is reported essential for detecting intracellular bacteria. However, it remains to be determined whether and how cGAS is involved in extracellular bacterial infection. Here, we report that cGAS is essential for mediating type I interferon (IFN) production in infection by multiple extracellular pathogens, including Pseudomonas aeruginosa, Klebsiella pneumoniae, and Staphylococcus aureus. In addition, the canonical cGAS-stimulator of interferon gene (STING)-IFN axis is required for protecting mice from P. aeruginosa-induced mouse acute pulmonary infection, confirmed in cGAS pathway-specific gene deficiency mouse models. cGAS -/- and STING -/- mice exhibited reduced type I IFNs production, excessive inflammatory response accompanied with decreased resistance to P. aeruginosa challenge. Unfolded protein response was also modulated by cGAS through IRF3 and type I IFNs under P. aeruginosa infection. Collectively, these findings uncover the importance of cGAS in initiating immune responses against extracellular bacterial infection.

Cardiac telocytes inhibit cardiac microvascular endothelial cell apoptosis through exosomal miRNA-21-5p-targeted cdip1 silencing to improve angiogenesis following myocardial infarction.

Promotion of cardiac angiogenesis in ischemic myocardium is a critical strategy for repairing and regenerating the myocardium after myocardial infarction (MI). Currently, effective methods to aid in the survival of endothelial cells, to avoid apoptosis in ischemic myocardium and to achieve long-term cardiac angiogenesis are still being pursued. Here, we investigated whether cardiac telocyte (CT)-endothelial cell communication suppresses apoptosis and promotes the survival of endothelial cells to facilitate cardiac angiogenesis during MI. Methods: CT exosomes were isolated from CT conditioned medium, and their miRNA profile was characterized by small RNA sequencing. A rat model of left anterior descending coronary artery ligation (LAD)-mediated MI was assessed with histology for infarct size and fibrosis, immunostaining for angiogenesis and cell apoptosis and echocardiography to evaluate the therapeutic effects. Cardiac microvascular endothelial cells (CMECs) and the LAD-MI model treated with CT exosomes or CT exosomal miRNA-21-5p in vitro and in vivo were assessed with cellular and molecular techniques to demonstrate the underlying mechanism. Results: CTs exert therapeutic effects on MI via the potent paracrine effects of CT exosomes to facilitate the inhibition of apoptosis and survival of CMECs and promote cardiac angiogenesis. A novel mechanism of CTs is revealed, in which CT-endothelial cell communication suppresses apoptosis and promotes the survival of endothelial cells in the pathophysiological myocardium. CT exosomal miRNA-21-5p targeted and silenced the cell death inducing p53 target 1 (Cdip1) gene and thus down-regulated the activated caspase-3, which then inhibited the apoptosis of recipient endothelial cells under ischemic and hypoxic conditions, facilitating angiogenesis and regeneration following MI. Conclusions: The present study is the first to show that CTs inhibit cardiac microvascular endothelial cell apoptosis through exosomal miRNA-21-5p-targeted Cdip1 silencing to improve angiogenesis in myocardial infarction. It is believed that these novel findings and the discovery of cellular and molecular mechanisms will provide new opportunities to tailor novel cardiac cell therapies and cell-free therapies for the functional and structural regeneration of the injured myocardium.

Cxcr4 and Sdf-1 are critically involved in the formation of facial and non-somitic neck muscles.

The present study shows that the CXCR4/SDF-1 axis regulates the migration of second branchial arch-derived muscles as well as non-somitic neck muscles. Cxcr4 is expressed by skeletal muscle progenitor cells in the second branchial arch (BA2). Muscles derived from the second branchial arch, but not from the first, fail to form in Cxcr4 mutants at embryonic days E13.5 and E14.5. Cxcr4 is also required for the development of non-somitic neck muscles. In Cxcr4 mutants, non-somitic neck muscle development is severely perturbed. In vivo experiments in chicken by means of loss-of-function approach based on the application of beads loaded with the CXCR4 inhibitor AMD3100 into the cranial paraxial mesoderm resulted in decreased expression of Tbx1 in the BA2. Furthermore, disrupting this chemokine signal at a later stage by implanting these beads into the BA2 caused a reduction in MyoR, Myf5 and MyoD expression. In contrast, gain-of-function experiments based on the implantation of SDF-1 beads into BA2 resulted in an attraction of myogenic progenitor cells, which was reflected in an expansion of the expression domain of these myogenic markers towards the SDF-1 source. Thus, Cxcr4 is required for the formation of the BA2 derived muscles and non-somitic neck muscles.

Cardiac telocytes exist in the adult Xenopus tropicalis heart.

Recent research has revealed that cardiac telocytes (CTs) play an important role in cardiac physiopathology and the regeneration of injured myocardium. Recently, we reported that the adult Xenopus tropicalis heart can regenerate perfectly in a nearly scar-free manner after injury via apical resection. However, whether telocytes exist in the X tropicalis heart and are affected in the regeneration of injured X tropicalis myocardium is still unknown. The present ultrastructural and immunofluorescent double staining results clearly showed that CTs exist in the X tropicalis myocardium. CTs in the X tropicalis myocardium were mainly twined around the surface of cardiomyocyte trabeculae and linked via nanocontacts between the ends of the telopodes, forming a three-dimensional network. CTs might play a role in the regeneration of injured myocardium.

BDNF and NGF signals originating from sensory ganglia promote cranial motor axon growth.

After exiting the hindbrain, branchial motor axons reach their targets in association with sensory ganglia. The trigeminal ganglion has been shown to promote motor axon growth from rhombomeres 2/3 and 4/5, but it is unknown whether this effect is ganglion specific and through which signals it is mediated. Here, we addressed these questions by co-cultures of ventral rhombomere 8 explants with cranial and spinal sensory ganglia in a collagen gel matrix. Our results show that all cranial sensory ganglia and even a trunk dorsal root ganglion can promote motor axon growth and that ganglia isolated from older embryos had a stronger effect on the axonal growth than younger ones. We found that brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are necessary and sufficient for this effect. Altogether, our results demonstrate that the promoting effect of sensory ganglia on cranial motor axon growth is stage dependent, but not ganglion specific and is mediated by BDNF and NGF signals.

Research Progress of Shengjiangsan in Treating Systemic Inflammatory Response Syndrome / 中国实验方剂学杂志

Shengjiangsan was recorded in a medical book Treatise on Cold-induced Disorders and Plague written in the Qing Dynasty. This prescription， consisting of four drugs： Bombyx， cicada slough， Turmeric and Rhubarb， is simple but effective in regulating Qi and eliminating pathogenic factors. In recent years， the researches on the mechanism of this prescription have been continuously expanded and deepened. According to the collected data， Shengjiangsan is widely used in the treatment of various clinical diseases. The concept of systemic inflammatory response syndrome （SIRS） was first proposed in the 1990s， and it refers to the pathophysiological state caused by self-amplified cascade inflammatory response and inflammatory factor storm arising from infectious or non-infectious factors. In recent years， the treatment of SIRS has gradually become the current focus and hotspot. Patients with severe acute respiratory syndrome （SARS） and novel coronavirus pneumonia （COVID-19） often die from SIRS progression to multiple organ dysfunction syndrome （MODS） or even multiple organ failure （MOF）. Interleukin -1 receptor antagonist， anti-bradykinin， platelet activating factor receptor antagonist and other commonly used drugs in clinical treatment of SIRS have not achieved satisfactory results， so it is urgent to find drugs to improve SIRS status. Shengjiangsan is recommended as an initial prescription in traditional Chinese medicine diagnosis and treatment plan for SARS and COVID-19， and its antiviral effect may be related to preventing SIRS from transforming into MODS. Pharmacological studies have shown that Shengjiangsan can regulate the immune imbalance of SIRS to achieve a balance by intervening various inflammatory factors and their signaling pathways. At present， there are few reports on the treatment of SIRS with Shengjiangsan. Therefore， the theoretical analysis of Shengjiangsan and its clinical research and pharmacological mechanism in the treatment of SIRS are discussed here to broaden the thinking for clinical practice and experimental research.

Early moderate exercise benefits myocardial infarction healing via improvement of inflammation and ventricular remodelling in rats.

Thus far, the cellular and molecular mechanisms related to early (especially within 24 hours after acute myocardial infarct (MI)) exercise-mediated beneficial effects on MI have not yet been thoroughly established. In the present study, we demonstrated that acute MI rats that underwent early moderate exercise training beginning one day after MI showed no increase in mortality and displayed significant improvements in MI healing and ventricular remodelling, including an improvement in cardiac function, a decrease in infarct size, cardiomyocyte apoptosis, cardiac fibrosis and cardiomyocyte hypertrophy, and an increase in myocardial angiogenesis, left ventricular wall thickness and the number of cardiac telocytes in the border zone. Integrated miRNA-mRNA profiling analysis performed by the ingenuity pathway analysis system revealed that the inhibition of the TGFB1 regulatory network, activation of leucocytes and migration of leucocytes into the infarct zone comprise the molecular mechanism underlying early moderate exercise-mediated improvements in cardiac fibrosis and the pathological inflammatory response. The findings of the present study demonstrate that early moderate exercise training beginning one day after MI is safe and leads to significantly enhanced MI healing and ventricular remodelling. Understanding the mechanism behind the positive effects of this early training protocol will help us to further tailor suitable cardiac rehabilitation programmes for humans.

Effects of PNPLA3, TM6SF2 gene polymorphisms and its interactions with smoking and alcohol drinking on hepatitis B virus-associated hepatocellular carcinoma / 中华流行病学杂志

Objective To explore the SNP effects ofpatatin-like phospholipase domain which containing 3 (PNPLA3),transmembrane 6 superfamily member 2 (TM6SF2) gene,environmental effects of smoking,alcohol drinking and interaction between gene-gene,gene-environment and drinking-smoking on hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC).Methods We collected anticoagulant peripheral blood from patients of HBV-HCC,chronic hepatitis B (CHB),liver cirrhosis (LC) and from healthy controls to detect the single nucleotide polymorphism (SNP) of patatin-like phospholipase domain containing 3 (PNPLA3) gene loci rs738409 and transmembrane 6 superfamily member 2 (TM6SF2) gene loci rs58542926,using the flight mass spectrometry method.The optimal assignment value of gene polymorphisms was defined by using the online SNP stats.Hardy-Weinberg (H-W) balance was tested for SNP.Effects of the genetic and environmental factors to HBV-HCC were analyzed by using the multiple classification logistic regression method.The gene-gene,gene-smoking and alcohol drinking interaction effects were investigated by Fork-Life analysis and binary logistic regression methods.Results The frequency distribution of CHB group rs738409 loci seemed not in conformity with the H-W balance (x2=11.980,P＜0.005).Two loci frequency distributions in the other groups were all in accordandce with the H-W balance.After adjusting for influences on age and sex and comparing to the healthy group,the rs58542926 mutation appeared as OR=1.659,95％CI:1.026-2.684,P=0.039,in the HBV-HCC group.When comparing to CHB group,the HBV-HCC group presented that drinking as OR=1.680,95％CI:1.121-2.519,P=0.012.When comparing to the LC group,the ORs of drinking and smoking were 1.539 (1.071-2.213) and 1.453 (1.005-2.099) respectively,in the HBV-HCC group.When comparing to the CHB + LC group,interactions between the HBV-HCC group were found rs738409 and rs58542926 on additive model OR=1.548 (U=1.885,P=0.029) and OR=1.658 (P=0.024) on logistic regression model while drinking was rs738409 on interaction additive model with OR=1.811(U=1.965,P=0.024).As for drinking and mutation of rs738409,the multiplication model of logistic regression showed no statistically significant differences.Interaction between smoking and drinking appeared as OR=1.756 (P＜0.001) in the logistics regression multiplication model.Conclusions Factors as mutation of TM6SF2,smoking and drinking all appeared as risk factors for HBV-HCC.Mutations of both PNPLA3 and TM6SF2,together with smoking and drinking all served as risk factors for HBV-HCC.However,the mutation of single PNPLA3 appeared as a protective factor on HBV-HCC.

Effects of PNPLA3, TM6SF2 gene polymorphisms and its interactions with smoking and alcohol drinking on hepatitis B virus-associated hepatocellular carcinoma / 中华流行病学杂志

Objective To explore the SNP effects ofpatatin-like phospholipase domain which containing 3 (PNPLA3),transmembrane 6 superfamily member 2 (TM6SF2) gene,environmental effects of smoking,alcohol drinking and interaction between gene-gene,gene-environment and drinking-smoking on hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC).Methods We collected anticoagulant peripheral blood from patients of HBV-HCC,chronic hepatitis B (CHB),liver cirrhosis (LC) and from healthy controls to detect the single nucleotide polymorphism (SNP) of patatin-like phospholipase domain containing 3 (PNPLA3) gene loci rs738409 and transmembrane 6 superfamily member 2 (TM6SF2) gene loci rs58542926,using the flight mass spectrometry method.The optimal assignment value of gene polymorphisms was defined by using the online SNP stats.Hardy-Weinberg (H-W) balance was tested for SNP.Effects of the genetic and environmental factors to HBV-HCC were analyzed by using the multiple classification logistic regression method.The gene-gene,gene-smoking and alcohol drinking interaction effects were investigated by Fork-Life analysis and binary logistic regression methods.Results The frequency distribution of CHB group rs738409 loci seemed not in conformity with the H-W balance (x2=11.980,P＜0.005).Two loci frequency distributions in the other groups were all in accordandce with the H-W balance.After adjusting for influences on age and sex and comparing to the healthy group,the rs58542926 mutation appeared as OR=1.659,95％CI:1.026-2.684,P=0.039,in the HBV-HCC group.When comparing to CHB group,the HBV-HCC group presented that drinking as OR=1.680,95％CI:1.121-2.519,P=0.012.When comparing to the LC group,the ORs of drinking and smoking were 1.539 (1.071-2.213) and 1.453 (1.005-2.099) respectively,in the HBV-HCC group.When comparing to the CHB + LC group,interactions between the HBV-HCC group were found rs738409 and rs58542926 on additive model OR=1.548 (U=1.885,P=0.029) and OR=1.658 (P=0.024) on logistic regression model while drinking was rs738409 on interaction additive model with OR=1.811(U=1.965,P=0.024).As for drinking and mutation of rs738409,the multiplication model of logistic regression showed no statistically significant differences.Interaction between smoking and drinking appeared as OR=1.756 (P＜0.001) in the logistics regression multiplication model.Conclusions Factors as mutation of TM6SF2,smoking and drinking all appeared as risk factors for HBV-HCC.Mutations of both PNPLA3 and TM6SF2,together with smoking and drinking all served as risk factors for HBV-HCC.However,the mutation of single PNPLA3 appeared as a protective factor on HBV-HCC.

The hypaxial origin of the epaxially located rhomboid muscles.

In vertebrates, skeletal muscles of the body are made up of epaxial and hypaxial muscles based on their innervation and relative position to the vertebral column. The epaxial muscles are innervated by the dorsal branches of the spinal nerves and comprise the intrinsic (deep) back muscles, while the hypaxial muscles are innervated by the ventral branches of the spinal nerves including the plexus and consist of a heterogeneous group of intercostal, abdominal, and limb as well as girdle muscles. The canonical view holds that the epaxial muscles are derived from the medial halves of the somites, whereas the hypaxial muscles are all derived from the lateral somitic halves. The rhomboid muscles are situated dorsal to the vertebral column and therefore in the domain typically occupied by epaxial muscles. However, they are innervated by a ventral branch of the brachial plexus called the N. dorsalis scapulae. Due to the apparent inappropriate position of the muscle in relation to its innervation we investigated its origin to help clarify this issue. To study the embryonic origin of the rhomboid muscles, we followed derivatives of the medial and lateral somite halves using quail-chick chimeras. Our results showed that the rhomboid muscles are made up of cells derived mainly from the lateral portion of the somite. Therefore the rhomboid muscles which lie within the epaxial domain of the body, originate from the hypaxial domain of the somites. However their connective tissue is derived from both medial and lateral somites.

The unique axon trajectory of the accessory nerve is determined by intrinsic properties of the neural tube in the avian embryo.

The accessory nerve is a cranial nerve, composed of only motor axons, which control neck muscles. Its axons ascend many segments along the lateral surface of the cervical spinal cord and hindbrain. At the level of the first somite, they pass ventrally through the somitic mesoderm into the periphery. The factors governing the unique root trajectory are unknown. Ablation experiments at the accessory nerve outlet points have shown that somites do not regulate the trajectory of the accessory nerve fibres. Factors from the neural tube that may control the longitudinal pathfinding of the accessory nerve fibres were tested by heterotopic transplantations of an occipital neural tube to the cervical and thoracic level. These transplantations resulted in a typical accessory nerve trajectory in the cervical and thoracic spinal cord. In contrast, cervical neural tube grafts were unable to give rise to the typical accessory nerve root pattern when transplanted to occipital level. Our results show that the formation of the unique axon root pattern of the accessory nerve is an intrinsic property of the neural tube.

SDF-1 controls the muscle and blood vessel formation of the somite.

Stromal-cell-derived factor-1 (SDF-1), the only ligand of the chemokine receptor CXCR4, is involved in skeletal muscle development. However, its role in the proliferation, differentiation and migration of somite cells is not well understood. Here, we investigated its function during somite development in chicken embryos by using gain-of-function and loss-of-function experiments. Overexpression of SDF-1 was performed by electroporating SDF-1 constructs into the ventrolateral part of the somite, or by injecting SDF-1-expressing cells into the somites of stages HH14-16 chicken embryos. We found that enhanced SDF-1 signaling induced cell proliferation in the somite. This resulted in an increase in number of both myotomal and endothelial cells. In contrast, inhibition of SDF-1/CXCR4 signaling led to a reduction of myotomal cells. Injection of SDF-1 producing cells into the somite induced ectopic localization of myotomal cells in the sclerotome. Although many SDF-1-expressing somite cells colonized the limb, only a few of them developed into muscle cells. This resulted in a reduction of the limb muscle mass. This means that most myogenic progenitors were stopped on their migration towards the limb due to the high concentration of the SDF-1 signal in the somite. Most of the SDF-1-expressing somite cells found in the limb were of endothelial cell fate and they contributed to the increase in limb blood vessels. These results reveal that SDF-1 promotes the proliferation of both myogenic and angiogenic progenitor cells of the somite and controls myotome formation. Furthermore, SDF-1 controls muscle and blood vessel formation in the limb in different ways.

A novel interaction between ATOH8 and PPP3CB.

ATOH8 is a bHLH transcription factor playing roles in a variety of developmental processes such as neurogenesis, differentiation of pancreatic precursor cells, development of kidney and muscle, and differentiation of endothelial cells. PPP3CB belongs to the catalytic subunit of the serine/threonine phosphatase, calcineurin, which can dephosphorylate its substrate proteins to regulate their physiological activities. In our study, we demonstrated that ATOH8 interacts with PPP3CB in vitro with different approaches. We show that the conserved catalytic domain of PPP3CB interacts with both the N-terminus and the bHLH domain of ATOH8. Although the interaction domain of PPP3CB is conserved among all isoforms of calcineurin A, ATOH8 selectively interacts with PPP3CB instead of PPP3CA, probably due to the unique proline-rich region present in the N-terminus of PPP3CB, which controls the specificity of its interaction partners. Furthermore, we show that inhibition of the interaction with calcineurin inhibitor, cyclosporin A (CsA), leads to the retention of ATOH8 to the cytoplasm, suggesting that the interaction renders nuclear localization of ATOH8 which may be critical to control its activity as transcription factor.

Development of the shoulder girdle musculature.

The muscles of the shoulder region are important for movements of the upper limbs and for stabilizing the girdle elements by connecting them to the trunk. They have a triple embryonic origin. First, the branchiomeric shoulder girdle muscles (sternocleidomastoideus and trapezius muscles) develop from the occipital lateral plate mesoderm using Tbx1 over the course of this development. The second population of cells constitutes the superficial shoulder girdle muscles (pectoral and latissimus dorsi muscles), which are derived from the wing premuscle mass. This muscle group undergoes a two-step development, referred to as the "in-out" mechanism. Myogenic precursor cells first migrate anterogradely into the wing bud. Subsequently, they migrate in a retrograde manner from the wing premuscle mass to the trunk. SDF-1/CXCR4 signaling is involved in this outward migration. A third group of shoulder muscles are the rhomboidei and serratus anterior muscles, which are referred to as deep shoulder girdle muscles; they are thought to be derived from the myotomes. It is, however, not clear how myotome cells make contact to the scapula to form these two muscles. In this review, we discuss the development of the shoulder girdle muscle in relation to the different muscle groups.

The lateral plate mesoderm: a novel source of skeletal muscle.

It has been established in the last century that the skeletal muscle cells of vertebrates originate from the paraxial mesoderm. However, recently the lateral plate mesoderm has been identified as a novel source of the skeletal muscle. The branchiomeric muscles, such as masticatory and facial muscles, receive muscle progenitor cells from both the cranial paraxial mesoderm and lateral plate mesoderm. At the occipital level, the lateral plate mesoderm is the sole source of the muscle progenitors of the dorsolateral neck muscle, such as trapezius and sternocleidomastoideus in mammals and cucullaris in birds. The lateral plate mesoderm requires a longer time for generating skeletal muscle cells than the somites. The myogenesis of the lateral plate is determined early, but not cell autonomously and requires local signals. Lateral plate myogenesis is regulated by mechanisms controlling the cranial myogenesis. The connective tissue of the lateral plate-derived muscle is formed by the cranial neural crest. Although the cranial neural crest cells do not control the early myogenesis, they regulate the patterning of the branchiomeric muscles and the cucullaris muscle. Although satellite cells derived from the cranial lateral plate show distinct properties from those of the trunk, they can respond to local signals and generate myofibers for injured muscles in the limbs. In this review, we key feature in detail the muscle forming properties of the lateral plate mesoderm and propose models of how the myogenic fate may have arisen.