SummaryNervous systems are constructed from a deep repertoire of neuron types but the underlying gene expression programs that specify individual neuron identities are poorly understood. To address this deficit, we have produced an expression profile of all 302 neurons of the C. elegans nervous system that matches the single cell resolution of its anatomy and wiring diagram. Our results suggest that individual neuron classes can be solely identified by combinatorial expression of specific gene families. For example, each neuron class expresses unique codes of ∼23 neuropeptide-encoding genes and ∼36 neuropeptide receptors thus pointing to an expansive “wireless” signaling network. To demonstrate the utility of this uniquely comprehensive gene expression catalog, we used computational approaches to (1) identify cis-regulatory elements for neuron-specific gene expression across the nervous system and (2) reveal adhesion proteins with potential roles in synaptic specificity and process placement. These data are available at cengen.org and can be interrogated at the web application CengenApp. We expect that this neuron-specific directory of gene expression will spur investigations of underlying mechanisms that define anatomy, connectivity and function throughout the C. elegans nervous system.
In the fatal degenerative Duchenne muscular dystrophy (DMD), skeletal muscle is progressively replaced by fibrotic tissue. Here, we show that fibrinogen accumulates in dystrophic muscles of DMD patients and mdx mice. Genetic loss or pharmacological depletion of fibrinogen in these mice reduced fibrosis and dystrophy progression. Our results demonstrate that fibrinogen-Mac-1 receptor binding, through induction of IL-1, drives the synthesis of transforming growth factor- (TGF) by mdx macrophages, which in turn induces collagen production in mdx fibroblasts. Fibrinogen-produced TGF further amplifies collagen accumulation through activation of profibrotic alternatively activated macrophages. Fibrinogen, by engaging its ␣v3 receptor on fibroblasts, also directly promotes collagen synthesis. These data unveil a profibrotic role of fibrinogen deposition in muscle dystrophy.Supplemental material is available at http://www.genesdev.org.Received November 30, 2007; revised version accepted April 28, 2008. Duchenne muscular dystrophy (DMD) results from mutations in the gene coding for the protein dystrophin, which localizes at the inner face of the sarcolemma (Campbell 1995). Besides progressive muscle degeneration and inflammation, fibrotic transition of muscle tissue is critical in DMD as it progressively deteriorates locomotor capacity, posture maintenance, and the vital function of cardiac and respiratory muscles. Indeed, DMD individuals have a high degree of fibrosis increasing with age, which is reproduced in the diaphragm muscle of mdx mice (the mouse model of DMD) (Stedman et al. 1991). Importantly, the underlying mechanisms of fibrosis development within dystrophic muscle remain largely unknown.Fibrinogen is a soluble acute phase protein, which is released into the blood in response to stress. Apart from its key role in controlling blood loss following vascular injury, fibrinogen also extravasates at sites of inflammation or increased vascular permeability where it is immobilized and/or converted to fibrin (Rybarczyk et al. 2003) (from hereon we refer to both by the term "fibrin/ ogen"). We showed previously that mice with defective fibrinolysis exhibited impaired muscle regeneration after experimental injury (Suelves et al. 2002). In this study, we investigated the role of fibrin/ogen deposition in the development of fibrosis in dystrophic muscle. Results and DiscussionWe first analyzed fibrin/ogen deposition in muscles of DMD patients and its correlation with disease course. Compared with muscles of healthy individuals or of fibromyalgia patients, DMD muscles showed significant fibrin/ogen accumulation (Fig. 1A). Similarly, in mdx mice muscles, fibrin/ogen deposits were readily detectable after disease onset, while absent before disease onset (Fig. 1B,C). Thus, fibrin/ogen deposition is associated with muscle dystrophinopathy.Collagen deposition (fibrosis) was prominent in DMD muscles and particularly found in the same areas occupied by fibrin/ogen (Fig. 1D). To investigate the relationship between the e...
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