Structure-based models of cadherin-mediated cell adhesion: the evolution continues

Cadherins are glycoproteins that are responsible for homophilic, Ca²⁺-dependent cell-cell adhesion and play crucial roles in many cellular adhesion processes ranging from embryogenesis to the formation of neuronal circuits in the central nervous system. Many different experimental approaches have been used to unravel the molecular basis for cadherin-mediated adhesion. In particular, several high-resolution structures have provided models for cadherin-cadherin interactions that are illuminative in many respects yet contradictory in others. This review gives an overview of the structural studies of cadherins over the past decade while focusing on recent developments that reconcile some of the earlier findings.Received 7 January 2004; received after revision 24 February 2004; accepted 4 March 2004     

Mutations in MEGF10, a regulator of satellite cell myogenesis, cause early onset myopathy, areflexia, respiratory distress and dysphagia (EMARDD)

Infantile myopathies with diaphragmatic paralysis are genetically heterogeneous, and clinical symptoms do not assist in differentiating between them. We used phased haplotype analysis with subsequent targeted exome sequencing to identify MEGF10 mutations in a previously unidentified type of infantile myopathy with diaphragmatic weakness, areflexia, respiratory distress and dysphagia. MEGF10 is highly expressed in activated satellite cells and regulates their proliferation as well as their differentiation and fusion into multinucleated myofibers, which are greatly reduced in muscle from individuals with early onset myopathy, areflexia, respiratory distress and dysphagia.     

Vascular normalization in Rgs5-deficient tumours promotes immune destruction

The vasculature of solid tumours is morphologically aberrant and characterized by dilated and fragile vessels, intensive vessel sprouting and loss of hierarchical architecture. Constant vessel remodelling leads to spontaneous haemorrhages and increased interstitial fluid pressure in the tumour environment. Tumour-related angiogenesis supports tumour growth and is also a major obstacle for successful immune therapy as it prevents migration of immune effector cells into established tumour parenchyma. The molecular mechanisms for these angiogenic alterations are largely unknown. Here we identify regulator of G-protein signalling 5 (Rgs5) as a master gene responsible for the abnormal tumour vascular morphology in mice. Loss of Rgs5 results in pericyte maturation, vascular normalization and consequent marked reductions in tumour hypoxia and vessel leakiness. These vascular and intratumoral changes enhance influx of immune effector cells into tumour parenchyma and markedly prolong survival of tumour-bearing mice. This is the first demonstration, to our knowledge, of reduced tumour angiogenesis and improved immune therapeutic outcome on loss of a vascular gene function and establishes a previously unrecognized role of G-protein signalling in tumour angiogenesis.