Mesangial cells (mc) need to bind to a specific laminin (left, white line) to help form kidney capillary loops.

Students of cell biology could be excused for thinking that laminin biology evolved purely to vex them. Multiple different laminins—combinations of α, β, and γ subunits that make up at least 15 different versions of this heterotrimeric protein—are expressed in different places at different times, making a sensible analysis of this protein family a challenge. Most researchers have started with knockout experiments, but it is hardly surprising when a knockout defect correlates with the time and place of normal expression. Perhaps any laminin would suffice in the deleted laminin's place.

Now, Kikkawa et al. (page 187) find that this is not the case. They uncover a specialized function for the laminin α5 isoform (not to be confused with laminin-5) during development of the kidney glomerular basement membrane (GBM).

Laminins are key ingredients of basement membranes, which are both structural barriers and platforms for cellular interaction. GBM laminins present at the early, S-shape stage of kidney development contain the α1 subunit, but are replaced at the later capillary loop stage with ones that contain α5. When the researchers made mice lacking the laminin α5 chain (Lama5/) a few years ago, the mice died with a plethora of developmental glitches, including severe kidney defects. So the α1– α5 switch is critical for kidney development.

They have now studied this further using MR51—a chimeric laminin α chain that is mostly α5 but has the laminin G domains of α1. (G domains are specific to α laminin chains.) MR51 nicely rescues the GBM defect of the Lama5/ mutant, but capillary loops still are not made. A similar phenotype is seen in mice that lack mesangial cells, as these cells supply tension to maintain capillary loop structure. Although mesangial cells were present in the MR51, Lama5/ mice, they could not stick to the GBM.

Two proteins on mesangial cells, an integrin and the Lutheran blood group glycoprotein, were needed to grab onto the G domains of laminin α5. Thus, the laminin α5 isoform has both a general role in GBM integrity and a specialized role that allows mesangial cells to hold onto the GBM. ▪