Formation, maturation, stabilization, and functional efficacy of the neuromuscular junction (NMJ) are orchestrated by transsynaptic and autocrine signals embedded within the synaptic cleft. Here, we demonstrate that collagen XIII, a nonfibrillar transmembrane collagen, is another such signal. We show that collagen XIII is expressed by muscle and its ectodomain can be proteolytically shed into the extracellular matrix. The collagen XIII protein was found present in the postsynaptic membrane and synaptic basement membrane. To identify a role for collagen XIII at the NMJ, mice were generated lacking this collagen. Morphological and ultrastructural analysis of the NMJ revealed incomplete adhesion of presynaptic and postsynaptic specializations in collagen XIII-deficient mice of both genders. Strikingly, Schwann cells erroneously enwrapped nerve terminals and invaginated into the synaptic cleft, resulting in a decreased contact surface for neurotransmission. Consistent with morphological findings, electrophysiological studies indicated both postsynaptic and presynaptic defects in Col13a1 ؊/؊ mice, such as decreased amplitude of postsynaptic potentials, diminished probabilities of spontaneous release and reduced readily releasable neurotransmitter pool. To identify the role of collagen XIII at the NMJ, shed ectodomain of collagen XIII was applied to cultured myotubes, and it was found to advance acetylcholine receptor (AChR) cluster maturation. Together with the delay in AChR cluster development observed in collagen XIII-deficient mutants in vivo, these results suggest that collagen XIII plays an autocrine role in postsynaptic maturation of the NMJ. Altogether, the results presented here reveal that collagen XIII is a novel muscle-derived cue necessary for the maturation and function of the vertebrate NMJ.

Type XIII collagen is a type II transmembrane protein with three collagenous (COL1-3) and four noncollagenous domains (NC1-4). The human ␣1(XIII) chain contains altogether eight cysteine residues. We introduced point mutations to six of the most N-terminal cysteine residues, and we show here that the two cysteines 117 and 119 at the end of the N-terminal noncollagenous domain (NC1) are responsible for linking the three ␣1(XIII) chains together by means of interchain disulfide bonds. In addition, the intracellular and transmembrane domains have an impact on trimer formation, whereas the cysteines in the transmembrane domain and the COL1, the NC2, and the C-terminal NC4 domains do not affect trimer formation. We also suggest that the first three noncollagenous domains (NC1-3) harbor repeating heptad sequences typical of ␣-helical coiledcoils, whereas the conserved NC4 lacks a coiled-coil probability. Prevention of the coiled-coil conformation in the NC3 domain is shown here to result in labile type XIII collagen molecules. Furthermore, a new subgroup of collagenous transmembrane proteins, the Rattus norvegicus, Drosophila melanogaster, and Caenorhabditis elegans colmedins, is enlarged to contain also Homo sapiens collomin, and Pan troglodytes, Mus musculus, Tetraodon nigroviridis, and Dano rerio proteins. We suggest that there is a structurally varied group of collagenous transmembrane proteins whose biosynthesis is characterized by a coiled-coil motif following the transmembrane domain, and that these trimerization domains appear to be associated with each of the collagenous domains. In the case of type XIII collagen, the trimeric molecule has disulfide bonds at the junction of the NC1 and COL1 domains, and the type XIII collagen-like molecules (collagen types XXIII and XXV) and the colmedins are similar in that they all have a pair of cysteines in the same location. Moreover, furin cleavage at the NC1 domain can be expected in most of the proteins.The collagen family of proteins contains a continuously expanding subgroup of collagenous transmembrane proteins. For a protein to join this subfamily, it needs to fulfill two criteria; it should be a type II transmembrane protein with at least one collagenous domain. The currently accepted members are as follows: the type XIII collagen-like proteins (collagen types XIII, XXIII, and XXV), type XVII collagen, the class A macrophage scavenger receptor-like proteins (MSRs (macrophage scavenger receptors), MARCO (macrophage receptor with collagenous structures), and SRCL (scavenger receptor with C-type lectin)), ectodysplasin-A, and the colmedins (1, 2).We have studied the biosynthetic features of type XIII collagen by expressing it in insect cells using the baculovirus expression system, and we have demonstrated a disulfide-bonded homotrimeric molecule with three triple helical collagenous domains (3). Furthermore, the association of the three chains takes place in the N-terminal NC1 coiled-coil region, being followed by formation of the triple helix in an N-to C-terminal...

Background: Open cholecystectomy (OC) may still be necessary in surgical training to perform safe conversions of laparoscopic cholecystectomy (LC). Our aim was to study the outcome of LCs and OCs performed by surgical trainees. Methods: All consecutive cholecystectomies (1,581 LCs and 984 OCs) were retrospectively analyzed from 1995 until 2008. Operative complications were compared between the cholecystectomies performed by 20 trainees alone (n = 822), assisted operations (n = 754, trainees/specialist surgeons) and 9 specialists alone (n = 989). Results: Surgical trainees performed 787 (50%) LCs and 789 (80%) OCs either alone or assisted. The conversion rate of LC for trainees and specialist surgeons were 34 (7.0%) and 44 (5.5%), respectively. Complication rates and mortality were similar between the trainees and specialist surgeons. No bile duct injuries were associated with LCs or OCs performed by trainees alone. LCs were associated with 9 (0.57%) cases of bile leakage from cystic stump and 2 (0.13%) other bile duct injuries. Conclusion: Surgical trainees performed over half of our cholecystectomies with good results. The patient selection for LC versus OC was good, because no total transection of the common bile duct was observed in over 1,500 LC operations.