The renal glomerulus of mice lacking s–laminin/laminin β2: nephrosis despite molecular compensation by laminin β1

Abstract

S-laminin/laminin beta 2, a homologue of the widely distributed laminin B1/beta 1 chain, is a major component of adult renal glomerular basement membrane (GBM). Immature GBM bears beta 1, which is replaced by beta 2 as development proceeds. In mutant mice that lack beta 2, the GBM remains rich in beta 1, suggesting that a feedback mechanism normally regulates GBM maturation. The beta 2-deficient GBM is structurally intact and contains normal complements of several collagenous and noncollagenous glycoproteins. However, mutant mice develop massive proteinuria due to failure of the glomerular filtration barrier. These results support the idea that laminin beta chains are functionally distinct although they assemble to form similar structures. Laminin beta 2-deficient mice may provide a model for human congenital or idiopathic nephrotic syndromes.

Basement Membranes: Cell Scaffoldings and Signaling Platforms

“…Studies of GBM penetration by different-sized dextrans in rats provided early evidence that the basement membrane, rather than the slit, acts as the primary filtration barrier (Caulfield and Farquhar 1974). This was seemingly supported by the observation of the proteinuria that occurred following inactivation of either the gene (Lamb2) coding for the laminin b2 unit (a subunit found in kidney almost exclusively in the GBM) or podocyte-specific inactivation of the Lama5 gene (Noakes et al 1995b;Goldberg et al 2010). In humans, mutations of the Lamb2 gene cause Pierson syndrome, a disorder of congenital nephrosis and mesangial sclerosis associated with eye and (sometimes) neuromuscular junction abnormalities (Zenker et al 2004;Wuhl et al 2007).…”

“…By maturity, the laminin b2 subunit replaced b1 with a5 now the major a-subunit, and type IV collagen a3, a4, and a5 chains, produced by the podocytes, largely supplanting the embryonic a1 and a2 chains (Miner and Sanes 1994;Miner et al 1997;Abrahamson et al 2009). Failure of the laminin b1 to b2 transition was found to result in a normalappearing GBM associated with proteinuria whereas failure of replacement of laminin a1 by a5 was found to result in a failure of the glomerular tuft to develop within Bowman's space and a failure of normal organization of the glomerular cell types, effects likely caused by absence of a5-laminin receptor interactions (Noakes et al 1995b;Miner and Li 2000;Moulson et al 2001). The unique receptorbinding activities within the laminin a5 subunit, not found in the laminin a1 compensating subunit and required for glomerular vascularization, were localized to the LG1-3 domains that mediate integrin a3b1 and Lutheran receptor binding (Kikkawa et al 2002;Kikkawa and Miner 2006).…”

“…Inactivation of the laminin-a5 gene (Lama5) coding for the most widely expressed laminin subunit resulted in multiple embryonic defects including syndactyly, failure of neural tube closure, renal agenesis/failure of glomerulogenesis, and placental vessel malformations (Miner et al 1998). Inactivation of the genes coding for the laminin b2, a2, and a4 subunits, which are expressed later in a more tissue-restricted manner caused defects of the neuromuscular junction/glomerulus, skeletal muscle/peripheral nerve, and microvasculature/peripheral nerve, respectively, with survival into the post-natal period (Noakes et al 1995a;Noakes et al 1995b;Miyagoe et al 1997;Thyboll et al 2002;Wallquist et al 2005).…”

Whole-Genome Sequencing Coupled to Imputation Discovers Genetic Signals for Anthropometric Traits

“…A variant was considered to have musculoskeletal implications if (1) it is located within 100 kb or if it is an eQTL for a gene that has a relevant OMIM annotation, including association with human syndromes and animal models of relevant gene knock-outs, [64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83] such as abnormal skeletal, muscle, or cartilage development and abnormal body size or bone morphology, and (2) there are any skeletalrelated GWAS signals within 100 kb, such as bone mineral density. For example, rs35863206 (WEAF 22.35%, beta ¼ À0.0232, height p ¼ 5.91 3 10 À9 ) is a deletion located 53 kb upstream of PGR, which encodes the progesterone receptor protein and is correlated with rs147581469 (r 2 ¼ 0.72), a previously identified eQTL for PGR.…”

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…”