Aberrant differentiation of neuromuscular junctions in mice lacking s-laminin/laminin β2

Abstract

Synapse formation requires a complex interchange of information between the pre- and postsynaptic partners. At the skeletal neuromuscular junction, some of this information is contained in the basal lamina (BL), which runs through the synaptic cleft between the motor nerve terminal and the muscle fibre. During regeneration following injury, components of synaptic BL can trigger several features of postsynaptic differentiation in the absence of the nerve terminal, and of presynaptic differentiation in the absence of the muscle fibre. One nerve-derived component of synaptic BL, agrin, is known to affect postsynaptic differentiation, but no muscle-derived components have yet been shown to influence motor nerve terminals. A candidate for such a role is s-laminin (also called laminin beta 2), a homologue of the B1 (beta 1) chain of the widely distributed BL glycoprotein, laminin. s-Laminin is synthesized by muscle cells and concentrated in synaptic BL. In vitro, recombinant s-laminin fragments are selectively adhesive for motor neuron-like cells, inhibit neurite outgrowth promoted by other matrix molecules, and act as a 'stop signal' for growing neurites. By generating and characterizing mice with a targeted mutation of the s-laminin gene, we show here that s-laminin regulates formation of motor nerve terminals.

In VitroSynaptogenesis between the Somata of IdentifiedLymnaeaNeurons Requires Protein Synthesis But Not Extrinsic Growth Factors or Substrate Adhesion Molecules

“…Various cell and substrate adhesion molecules have been implicated in target cell selection and specific synapse formation (Chow, 1990;Z hu et al, 1994;Noakes et al, 1995). Although their involvement in axonal pathfinding and target cell selection is established, their precise role in synaptogenesis remains to be determined (Doherty and Walsh, 1992).…”

Cell biology of embryonic migration

“…(Costell et al, 1999) Tenascin C Extracellular matrix Total NC cells fail to disperse laterally (Tucker, 2001) Laminin γ1 Extracellular matrix Total Death at E5.5, lack of basement membranes (Smyth et al, 1999) Laminin β2 Extracellular matrix Total Postnatal death between P15-30, neuromuscular junctions and glomerular defects (Noakes et al, 1995a;Noakes et al, 1995b;Patton et al, 1997) Laminin α2 Extracellular matrix Total Death by 5 weeks postnatal, severe muscular dystrophy and peripheral neurophathy (Miyagoe et al, 1997) Laminin α2 (dy/dy) Extracellular matrix Spontaneous Adult lethality, severe muscular dystrophy and peripheral nerve dysmyelination (Patton et al, 1999;Patton et al, 1997) Laminin α3 Extracellular matrix Total Death at P2-3, epithelial adhesion defect (Ryan et al, 1999) Laminin α4 Extracellular matrix Total Transient microvascular defect with hemorrhages and misalignment of neuromuscular junctions (Patton et al, 2001;Thyboll et al, 2002) Laminin α5 Extracellular matrix Total Death at E14-E17, with placental vessel, neural (Miner et al, 1998;Miner and Li, 2000) Protein Function Type Phenotype Reference tube, limb, and kidney defects Fibronectin Extracellular matrix Total Death before E14.5, shortened anterior-posterior axes, deformed neural tubes, and defects in mesodermally derived tissues. (George et al, 1993) Collagen XVIII Extracellular matrix Total Eye abnormalities modeling Knoblock syndrome (Fukai et al, 2002) Extracellular matrix Total Basement membrane defects (Utriainen et al, 2004) Collagen XV Extracellular matrix Total Skeletal myopathy and cardiovascular defects (Eklund et al, 2001) betaglycan Extracellular matrix Total Embryonic lethality of heart and liver defects (Stenvers et al, 2003) Connexin 43 Cell-cell adhesion In vitro studies of cells from knockout mice…”

Identity, developmental restriction and reactivity of extralaminar cells capping mammalian neuromuscular junctions

“…Whether this is due to changes in the composition of the basal lamina at the neuromuscular junction Sanes et al, 1990;Cho et al, 1998) or other phenomena at endplates, such as endogenous electric fields (Betz et al, 1980;Kinnamon et al, 1985), remains to be established. Abnormalities of synaptic structure have been demonstrated in mutant mice that lack specific components of the synaptic basal lamina (Noakes et al, 1995;VanSaun et al, 2003). It will be interesting to examine the disposition of kranocytes in mutant mice lacking specific basal lamina components (or endogenous electric fields).…”