DISTINCT ROLES FOR LAMININ RECEPTORS IN THE DEVELOPMENT OF THE PERIPHERAL NERVOUS SYSTEM

Laminin‐2 is required for normal nerve development, as mutations in a2 laminin chain in dystrophia muscularis mice disrupt Schwann cell‐axon relationships before birth (axonal sorting) in the proximal peripheral nervous system, and after birth (paranode formation, myelination) in the distal peripheral nervous system. Which laminin receptor(s) mediate these different roles, and the reasons for district variability is unknown. We first show that compensation by laminin‐1 in nerves, but not roots of dystrophic mice may explain the regional differences in severity. Second, we investigated spatial, temporal, and hierarchy of expression of pure laminin receptors, integrin a6b1 and a6b4, and dystroglycan, in the normal Schwann cell lineage from precursors to mature Schwann cells. A combination of descriptive and loss‐of‐function experiments in vivo , and a synchronized myelinating model in vitro , showed that a6b1 has a prominent role in prenatal Schwann cell‐axon interactions. Conditional inactivation of b1 integrin in Schwann cells is not compensated before birth by other laminin receptors, and arrests most Schwann cells at early stages of axonal sorting. However, some Schwann cells escape the block and myelinate normally, possibly because of redundancy of laminin receptors after birth, during myelination. In support for this, dystroglycan and a6b4 appear perinatally both in normal and mutant mice, and are expressed by b1 deleted‐Schwann cells that form normal myelin. Interestingly, the onset of dystroglycan expression in a single fiber immediately precedes and correlates with the beginning of myelination, while a6b4 distribution is related to late myelination and possibly to maintenance of myelin sheaths. These data indicate that laminin support early axoglial interactions (axonal sorting) through b1‐class integrins, and late axoglial interactions through dystroglycan and a6b4 integrin.