Laminin regulates postnatal oligodendrocyte production by promoting oligodendrocyte progenitor survival in the subventricular zone

Abstract

The laminin family of extracellular matrix proteins are expressed broadly during embryonic brain development, but are enriched at ventricular and pial surfaces where laminins mediate radial glial attachment during corticogenesis. In the adult brain, however, laminin distribution is restricted, yet is found within the vascular basal lamina and associated fractones of the ventricular zone (VZ)-subventricular zone (SVZ) stem cell niche, where laminins regulate adult neural progenitor cell proliferation. It remains unknown, however, if laminins regulate the wave of oligodendrogenesis that occurs in the neonatal/early postnatal VZ-SVZ. Here we report that Lama2, the gene that encodes the laminin α2-subunit, regulates postnatal oligodendrogenesis. At birth, Lama2−/− mice had significantly higher levels of dying oligodendrocyte progenitor cells (OPCs) in the OPC germinal zone of the dorsal SVZ. This translated into fewer OPCs, both in the dorsal SVZ well as in an adjacent developing white matter tract, the corpus callosum. In addition, intermediate progenitor cells that give rise to OPCs in the Lama2−/− VZ-SVZ were mislocalized and proliferated nearer to the ventricle surface. Later, delays in oligodendrocyte maturation (with accompanying OPC accumulation), were observed in the Lama2−/− corpus callosum, leading to dysmyelination by postnatal day 21. Together these data suggest that pro-survival laminin interactions in the developing postnatal VZ-SVZ germinal zone regulate the ability, or timing, of oligodendrocyte production to occur appropriately.

Pathophysiology of the brain extracellular matrix: a new target for remyelination

“…Both humans and mice lacking the laminin α2 chain in the CNS display severe developmental abnormalities that are associated with deficient myelination 35,37 . Moreover, compared with wild-type animals, mice lacking this protein had increased numbers of dying oligodendrocyte precursor cells (OPCs) in the subventricular zone at birth and showed delayed maturation of oligodendrocytes in the corpus callosum 38 . In contrast to permissive laminins, fibronectin impedes the morphological differentiation of oligodendrocytes 39 as well as remyelination 40 .…”

Three-Dimensional Neural Spheroid Culture: AnIn VitroModel for Cortical Studies

“…In the present study, we chose laminin as a candidate ECM molecule because of its role in neurogenesis, cell migration, axon guidance, oligodendrocyte maturation, and axon myelination. 41,42 Laminin production in the cortical spheroids demonstrated the culture's advantage of inherent production of ECM, as well as the absence of introduced foreign materials.…”

The extracellular matrix: Focus on oligodendrocyte biology and targeting CSPGs for remyelination therapies

“…knockout of the laminin-2 a2 subunit show laminin promotes OPC survival in the subventricular zone at birth, and loss of the laminin a2 gene results in delayed oligodendrocyte maturation and dysmyelination at postnatal day 21(Relucio, Menezes, Miyagoe-Suzuki, Takeda, & Colognato, 2012). There is also in vitro evidence suggesting laminin-2 promotes OPC proliferation through stimulating cleavage of dystroglycan by MMPs.…”