Studies of laminin a2 chain deficient mice -muscle sparing, charaterization of Cib2 and defective spermatorgenesis

Mutations in the gene encoding laminin α2 chain, an extracellular matrix protein mainly expressed in the neuromuscular system, cause a severe form of muscular dystrophy, congenital muscular dystrophy type 1A (MDC1A). Laminin α2 chain is associated to the muscle fibers by two major receptors, where one of them, integrin α7β1, is diminished upon laminin α2 chain deficiency.
The majority of the skeletal muscles display severe dystrophic phenotypes upon laminin α2 chain absence, but we report a spared muscle group, the intrinsic laryngeal muscles (ILM). No evidence of muscle degeneration is detected and expression of various laminin chains is similar to that of limb muscles but sustained integrin α7B expression is noted. We therefore conclude that ILM are spared in the dy3K/dy3K mouse model of congenital muscular dystrophy type 1A.
The singling mediated by laminin α2 chain is poorly understood. To gain insight into the molecular mechanisms underlying MDC1A, we have performed gene expression profiling of laminin α2 chain deficient mouse limb muscle. One of the down-regulated genes encodes a protein called calcium and integrin binding protein 2 (Cib2) whose expression and function is unknown. However, the closely related Cib1 has been reported to bind integrin αIIb and may be involved in outside-in-signaling in platelets. Since Cib2 might be a novel integrin α7β1 binding protein in muscle, we have studied Cib2 expression in the developing and adult mouse. We demonstrate that Cib2 is a calcium binding protein that interacts with integrin α7Bβ1D. Thus, our data suggest a role for Cib2 as a cytoplasmic effector of integrin α7Bβ1D signaling in skeletal muscle.
Moreover, we have in the seminiferous tubules of laminin α2 chain deficient mice observed a defect in the timing of lumen formation, resulting in production of fewer spermatides. We also demonstrate that overexpression of laminin α1 chain in testis of dy3K/dy3K mice compensated for laminin α2 chain deficiency and significantly reversed the appearance of the histopathological features. We thus provide genetic data that laminin α chains are essential for normal testicular function in vivo.
In summary, the increased knowledge about the roles of laminin α2 chain in development and disease will hopefully help us to design novel therapeutic approaches for MDC1A.