Hemizygous deletion of chromosome 22q11 (del22q11) causes thymic, parathyroid, craniofacial and life-threatening cardiovascular birth defects in 1 in 4,000 infants. The del22q11 syndrome is likely caused by haploinsufficiency of TBX1, but its variable expressivity indicates the involvement of additional modifiers. Here, we report that absence of the Vegf164 isoform caused birth defects in mice, reminiscent of those found in del22q11 patients. The close correlation of birth and vascular defects indicated that vascular dysgenesis may pathogenetically contribute to the birth defects. Vegf interacted with Tbx1, as Tbx1 expression was reduced in Vegf164-deficient embryos and knocked-down vegf levels enhanced the pharyngeal arch artery defects induced by tbx1 knockdown in zebrafish. Moreover, initial evidence suggested that a VEGF promoter haplotype was associated with an increased risk for cardiovascular birth defects in del22q11 individuals. These genetic data in mouse, fish and human indicate that VEGF is a modifier of cardiovascular birth defects in the del22q11 syndrome.

Background: Polysialic acid (PSA) plays important roles in the developing and adult nervous system. Results: The interaction of PSA with myristoylated alanine-rich C kinase substrate (MARCKS) at the plasma membrane regulates neurite outgrowth. Conclusion:The MARCKS/PSA interaction regulates PSA-triggered signal transduction. Significance: Study of the molecular mechanisms underlying PSA-induced cellular responses helps to understand the functions of PSA in the nervous system.

Polysialic acid (PSA) is a large and highly negatively charged glycan that plays crucial roles in nervous system development and function in the adult. It has been suggested to facilitate cell migration, neurite outgrowth, and synaptic plasticity because its hydration volume could enhance flexibility of cell interactions. Evidence for receptors of PSA has so far been elusive. We now identified histone H1 as binding partner of PSA via a single-chain variable fragment antibody using an anti-idiotypic approach. Histone H1 directly binds to PSA as shown by ELISA. Surface biotinylation of cultured cerebellar neurons indicated an extracellular localization of histone H1. Immunostaining of live cerebellar neurons and Schwann cells confirmed that an extracellular pool of histone H1 colocalizes with PSA at the cell surface. Histone H1 was also detected in detergent-insoluble synaptosomal membrane subfractions and postsynaptic densities. When applied in vitro, histone H1 stimulated neuritogenesis, process formation and proliferation of Schwann cells, and migration of neural precursor cells via a PSA-dependent mechanism, further indicating that histone H1 is active extracellularly. These in vitro observations suggested an important functional role for the interaction between histone H1 and PSA not only for nervous system development but also for regeneration in the adult. Indeed, histone H1 improved functional recovery, axon regrowth, and precision of reinnervation of the motor branch in adult mice with femoral nerve injury. Our findings encourage investigations on the therapeutic potential of histone H1 in humans.

Summary The role of neutrophils in the immune response has long been regarded as mainly phagocytic, but recent publications have indicated the production of several cytokines by polymorphonuclear leucocytes (PMN). The results of the individual reports, however, vary considerably. In this study, we established a cytokine profile of pure human neutrophils and demonstrated that minor contamination of peripheral blood mononuclear cells (PBMCs) in PMN preparations can lead to false‐positive results. In our hands, peripheral blood PMN fail to produce the pro‐inflammatory cytokines interleukin (IL)‐1β, IL‐6 and tumour necrosis factor‐α (TNF‐α). Instead, they secrete large amounts of the chemokine IL‐8 and the anti‐inflammatory IL‐1 receptor antagonist (IL‐1ra). Additionally, PMN preparations of a high purity show production of the chemokines macrophage inflammatory protein (MIP)‐1α, MIP‐1β and growth‐related oncogene‐α (GRO‐α), as well as macrophage colony‐stimulating factor (M‐CSF). The neutrophil therefore represents a novelty by producing the antagonist of IL‐1β (i.e. IL‐1ra) in the absence of IL‐1β itself. To support our results, we differentiated stem cells from human cord blood into PMN and monocytes, respectively. These in vitro‐differentiated PMN showed the same cytokine profile as peripheral blood PMN lacking IL‐1β, while differentiated monocytes produced the expected IL‐1β in addition to IL‐1ra. The clear anti‐inflammatory nature of their cytokine profile enables PMN to antagonize pro‐inflammatory signals in experimental conditions. It is therefore possible that PMN play a key role in immune regulation by counteracting a dysregulation of the inflammatory process. Clinical studies, in which administration of recombinant G‐CSF had a favourable effect on the outcome of severe infections and even sepsis without worsening inflammation, could thus be explained by our results.