Basement membranes are thin extracellular matrices that separate epithelial and mesenchymal cells, and surround cells such as endothelial, muscle, and neural cells. Basement membranes are the first extracellular matrix to appear in development and are critical for organ development and tissue repair. They not only provide the scaffold for cells and cell layers, but they also play an essential role in morphogenesis that affects cell adhesion, migration, proliferation, and differentiation. Basement membranes consist of collagen IV, laminin, perlecan, nidogen/entactin, and other molecules, and they interact with one another to form supramolecular structures. Laminins are a family of large multidomain glycoproteins that are usually specific to basement membranes. Laminins perform a variety of biological activities, including promotion of cell adhesion, migration, differentiation, tumor cell invasion, and interactions with matrix molecules and cell surface receptors. Laminin-1 (also called laminin-111) is a heterotrimeric extracellular matrix protein composed of α1, β1, and γ1 chains and is crucial for early basement membrane assembly, as well as embryonic implantation and development. Laminin-1 promotes neurite outgrowth in various neuronal cells, and several active sites in the α1 and γ1 chains for neurite outgrowth have been identified. Mouse embryos that are deficient in Lama1 lack Reichert's membrane and die by embryonic day 7. In the central nervous system, however, the role of Lama1 is unknown. To study the in vivo role of Lama1 in the CNS, we generated conditional Lama1 knockout (Lama1CKO) mice in the epiblast lineage using Sox2-Cre mice in collaboration with Dr. Eri Arikawa-Hirasawa. These Lama1CKO mice survived, but displayed behavioral disorders and impaired formation of the cerebellum. Deficiency of Lama1 in the pial basement membrane of the meninges resulted in defects in the conformation of the meninges. During cerebellar development, Lama1 deficiency also caused a decrease in the proliferation and migration of granule cell precursors, disorganization of Bergmann glial fibers and endfeet, and a transient reduction in the activity of Akt. A marked reduction in the number of dendritic processes in Purkinje cells was observed in Lama1CKO mice. Together, these results indicate that Lama1 is required for cerebellar development and function. During the creation of transgenic mice to study the role of perlecan, a basement membrane component, we found that one of the transgenic lines developed tremor in the hindlimbs. We designated this mouse model as furue (fru/fru). We subsequently identified that the furue mutation was caused by a transgene insertion into the teneurin-4 (Ten-4/Odz4) gene, which encoded a transmembrane protein of unknown function. Ten-4 was strongly expressed in the spinal cord of wild-type mice and was induced during normal oligodendrocyte differentiation. In contrast, the furue mice showed no expression of Ten-4. In the spinal cord of the furue mice, myelination of small diameter axons was dramatically reduced and differentiation of oligodendrocytes in the CNS was inhibited. The tremor phenotype in fur/fur mice was predominantly observed in the hindlimbs. The dorsal column of the fur/fur spinal cord showed severe defects in myelin formation in the corticospinal tract and fasciculus gracilis. The corticospinal tract is one of the major motor tracts and consists of many small diameter axons. The fasciculus gracilis is the region from which the small diameter axons of the lower body's sensory neurons ascend. Therefore, defects in myelination of small diameter axons in the corticospinal tract and the fasciculus gracilis are likely the cause of the hindlimb-dominant tremors in the fur/fur mice. In patients with multiple sclerosis, a dysmyelinating disease, small diameter axons are selectively damaged in the corticospinal and sensory tracts of the spinal cord. Ten-4 may therefore play an important role in multiple sclerosis.
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