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P. muscle fibers, and adipocytes. Most mature BMs contain laminin, type IV collagen, heparan sulfate core protein perlecan, and nidogen (entactin). Laminins are heterotrimeric multidomain glycoproteins composed of , , and chains. They are major structural elements of all BMs, but they also serve as signaling molecules through their interactions with cell surface receptors. In the BM, laminins are believed to exist as a polymerized two-dimensional network anchored around the cell surface via receptors, such as integrins, at the globular C-terminal domain name of the chain. In most mature BMs, type IV collagen is usually thought to form a more stable and rigid T-3775440 hydrochloride network, while nidogen is usually believed to serve as a bridge joining the independent networks of laminin and type IV collagen (4, 46). To date, five , three , and three chains Rabbit Polyclonal to RAB41 have been identified T-3775440 hydrochloride (4), which exist in at least 12 heterotrimeric combinations (laminin isoforms 1 to 12) with different tissue distributions and functions. For instance, deficiency of the epithelium-specific laminin-5 (3:3:2) causes junctional epidermolysis bullosa (18, 35, 36), mutations in the 2 2 chain gene cause muscular dystrophy in both mice and humans (12, 47, 48), and lack of the widely expressed 5 chain in mice leads to multiple developmental defects, including exencephaly, syndactyly, and placental defects (28). The laminin 4 chain (6, 13, 15, 27) is usually a component chain of laminin-8 (4:1:1) and laminin-9 (4:2:1) (29) and is widely distributed in vascular endothelial BMs of several tissues, as well as in BMs of the perineurium of peripheral nerves, heart, developing skeletal muscle, and developing kidney (6, 13, T-3775440 hydrochloride 23, 31). It has also been described in non-BM locations, e.g., in thrombocytes (7). The developmental expression patterns of the laminin chains are complicated and not fully characterized in all tissues. In the capillaries of skeletal muscle, laminin 4 is usually first detected at embryonic day 11 (E11) and is retained at this site throughout development and into adulthood (13, 31). Laminin 5 is the other major laminin chain known to occur in capillary BMs of muscle and most other tissues, but it appears later in development, at around 3 to 4 4 weeks postnatally (31, 43). One study recently reported that this laminin 2 chain was associated with capillaries in adult skeletal muscle (44), while an earlier study did not detect this chain in that particular location (31). Laminin 1 and 2 chains were previously reported as being expressed in the endothelial BMs of central nervous system capillaries (16, 34, 45), but it was recently shown that these chains are located in the parenchymal BM of the astrocyte endfeet surrounding these capillaries, and not in the endothelial BM (40). Since the laminin 2, 3, 2, and 3 chains have not been found in capillaries (14, 19, 31), laminin-8 is usually presumably the only laminin trimer in the capillary BMs of most embryonic and neonatal tissues. The specific biological functions of laminin 4 and the isoforms made up of this chain (laminin-8 and -9) are still poorly understood, and no human disease has been associated with absence or abnormalities in the laminin 4 chain. Its in vivo distribution provides some hints about possible functions. In particular, the widespread and exclusive expression of laminin 4 in basement membranes of developing microvessels suggests a role in angiogenic processes. We have previously shown that endothelial cells can bind laminin-8 through integrins 61.