Schwann Cell-Specific Ablation of Laminin γ1 Causes Apoptosis and Prevents Proliferation

Abstract

To investigate the function of laminin in peripheral nerve development, we specifically disrupted the laminin ␥1 gene in Schwann cells. Disruption of laminin ␥1 gene expression resulted in depletion of all other laminin chains known to be expressed in Schwann cells. Schwann cells lacking laminin do not extend processes required for initiating axonal sorting and mediating axon-Schwann cell interaction. They fail to downregulate Oct-6 and arrest at the premyelinating stage. The impaired axon-Schwann cell interaction prevents phosphorylation of ␤-neuregulin-1 receptors and results in decreased cell proliferation. Postnatally, laminin-null Schwann cells exhibit reduced phosphatidylinositol 3 (PI3)-kinase activity and activation of caspase cascades, leading to apoptosis. Injection of a laminin peptide into mutant sciatic nerves partially restores PI3-kinase activity and reduces apoptotic signals. These results demonstrate the following: (1) that laminin initiates axonal sorting and mediates axon-Schwann cell interactions required for Schwann cell proliferation and differentiation, and (2) that laminin provides a PI3-kinase/Akt-mediated Schwann cell survival signal.

Regulation of Schwann cell function by the extracellular matrix

“…PI3-kinase activation in laminin-deficient Schwann cells is severely reduced (Yu et al, 2005), which may be a consequence of the impaired differentiation (Taveggia et al, 2005). However, disruption of laminins may also contribute to the reduction of this survival pathway, which results in apoptosis based on the following observations.…”

“…Mouse Schwann cells lacking the laminin g1 subunit lose all laminin expression, and mice carrying this mutation show a severe phenotype (Yu et al, 2005(Yu et al, , 2007. These mice exhibit tremor, muscle weakness, and hind limb paralysis, preventing most of them from reaching adulthood.…”

“…During late embryonic to perinatal stages (E15 to P0 in mice), immature Schwann cells proliferate vigorously to rearrange, sort, and ensheath axons (Stewart et al, 1993) In laminin g1 mutant and dy2J/a4 double mutant mice, Schwann cell proliferation is dramatically decreased during this developmental stage (Yang et al, 2005;Yu et al, 2005) (Fig. 2A).…”

Development of the Schwann cell lineage: From the neural crest to the myelinated nerve

“…In rats, while proliferation is high in Schwann cell precursors, the maximum rate of division occurs in immature Schwann cells at E18/19 (Stewart et al, 1993). Similarly, in mice, proliferation is high at the Schwann cell precursor stage (E13), but significantly increases and reaches a peak at the immature Schwann cell stage (E15 onwards) (Yu et al, 2005). Schwann cell proliferation has been shown to be axonally induced in in vitro studies, where direct contact with neurites and neurite fractions were shown to induce cell division in Schwann cells (Salzer et al, 1980).…”

Basement Membranes: Cell Scaffoldings and Signaling Platforms

“…An evolving but incomplete model holds that laminin (or basement membrane) ligation of b1 integrins promotes lammellipodial extension and axonal interdigitation through alterations of the activated state of Rac1, Cdc42 and Rho/ Rho kinase. Laminins can affect both Schwann cell proliferation and process extension and proliferation whereas b1-integrins affect only the former (Yu et al 2005;Yu et al 2009). …”