Developmental activities of the complement pathway in migrating neurons

In recent years the notion that malfunctioning of the immune system may result in developmental brain diseases has emerged. However, the role of immune molecules in the developing brain has not been well explored. The complement pathway converges to cleave C3. Here we show that key proteins in the lectin arm of this pathway, MASP1, MASP2 and C3, are expressed in the developing cortex and that neuronal migration is impaired in knockout and knockdown mice. Molecular mimics of C3 cleavage products rescue the migration defects that have been seen following knockdown of C3 or Masp2. Pharmacological activation of the downstream receptors rescue Masp2 and C3 knockdown as well as C3 knockout. Therefore, we propose that the complement pathway is functionally important in migrating neurons of the developing cortex

Fibroblast growth factor signaling and basement membrane assembly are connected during epithelial morphogenesis of the embryoid body

Fibroblast growth factors and receptors are intimately connected to the extracellular matrix by their affinity to heparan sulfate proteoglycans. They mediate multiple processes during embryonic development and adult life. In this study, embryonic stem cell-derived embryoid bodies were used to model fibroblast growth factor signaling during early epithelial morphogenesis. To avoid redundancy caused by multiple receptors, we employed a dominant negative mutation of Fgfr2. Mutant-derived embryoid bodies failed to form endoderm, ectoderm, and basement membrane and did not cavitate. However, in mixed cultures they displayed complete differentiation induced by extracellular products of the normal cell. Evidence will be presented here that at least one of these products is the basement membrane or factors connected to it. It will be shown that in the mutant, collagen IV and laminin-1 synthesis is coordinately suppressed. We will demonstrate that the basement membrane is required for embryoid body differentiation by rescuing columnar ectoderm differentiation and cavitation in the mutant by externally added basement membrane proteins. This treatment induced transcription of Eomesodermin, an early developmental gene, suggesting that purified basement membrane proteins can activate inherent developmental programs. Our results provide a new paradigm for the role of fibroblast growth factor signaling in basement membrane formation and epithelial differentiation

Dendritic cell ICAM-1 strengthens synapses with CD8 T cells but is not required for their early differentiation

Summary: Lymphocyte priming in lymph nodes (LNs) was postulated to depend on the formation of stable T cell receptor (TCR)-specific immune synapses (ISs) with antigen (Ag)-presenting dendritic cells (DCs). The high-affinity LFA-1 ligand ICAM-1 was implicated in different ISs studied in vitro. We dissect the in vivo roles of endogenous DC ICAM-1 in Ag-stimulated T cell proliferation and differentiation and find that under type 1 polarizing conditions in vaccinated or vaccinia virus-infected skin-draining LNs, Ag-presenting DCs engage in ICAM-1-dependent stable conjugates with a subset of Ag-specific CD8 blasts. Nevertheless, in the absence of these conjugates, CD8 lymphocyte proliferation and differentiation into functional cytotoxic T cells (CTLs) and skin homing effector lymphocytes takes place normally. Our results suggest that although CD8 T cell blasts engage in tight ICAM-1-dependent DC-T ISs, firm ISs are dispensable for TCR-triggered proliferation and differentiation into productive effector lymphocytes