Schwann cell myelination occurred without basal lamina formation in laminin α2 chain‐null mutant ( dy 3K / dy 3K ) mice

147

211

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.

Section: Discussionmentioning

confidence: 68%

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

Yu¹,

Feltri²,

Wrabetz³

et al. 2005

147

211

“…mice lacking laminin ␣2 (Nakagawa et al, 2001). Myelination also occurred in the spinal roots of dy2J/a4 null mice lacking both laminin ␣2 and ␣4 chains, despite the absence of BM formation (Yang et al, 2005).…”

Section: Discussionmentioning

confidence: 95%

“…Performance in the behavioral tests was most severely compromised in the DKO, with trembling on the beam, ataxia, and slipping of the hindlimbs, and this was apparently attributable to a more prominent delay in the axonal segregation and a more pronounced lack of C-fibers relative to the Lam␣4 Ϫ/Ϫ mice. Laminin ␣4 is mainly expressed in immature, developing nerves (Patton et al, 1997;Nakagawa et al, 2001;Wallquist et al, 2002), which may account for the partial recovery of the axonal segregation observed in the Lama4 Ϫ/Ϫ mice over 1 year of age. Nonsegregated axons are prominent in both young and old DKO mice, signifying a permanent defect attributable to the absence of the normally constitutively expressed collagen XV.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Lack of Collagen XV Impairs Peripheral Nerve Maturation and, When Combined with Laminin-411 Deficiency, Leads to Basement Membrane Abnormalities and Sensorimotor Dysfunction

Rasi

Hurskainen²,

Kallio³

et al. 2010

Although the Schwann cell basement membrane (BM) is required for normal Schwann cell terminal differentiation, the role of BMassociated collagens in peripheral nerve maturation is poorly understood. Collagen XV is a BM zone component strongly expressed in peripheral nerves, and we show that its absence in mice leads to loosely packed axons in C-fibers and polyaxonal myelination. The simultaneous lack of collagen XV and another peripheral nerve component affecting myelination, laminin ␣4, leads to severely impaired radial sorting and myelination, and the maturation of the nerve is permanently compromised, contrasting with the slow repair observed in Lama4 Ϫ/Ϫ single knock-out mice. Moreover, the Col15a1 Ϫ/Ϫ ;Lama4 Ϫ/Ϫ double knock-out (DKO) mice initially lack C-fibers and, even over 1 year of age have only a few, abnormal C-fibers. The Lama4 Ϫ/Ϫ knock-out results in motor and tactile sensory impairment, which is exacerbated by a simultaneous Col15a1 Ϫ/Ϫ knock-out, whereas sensitivity to heat-induced pain is increased in the DKO mice. Lack of collagen XV results in slower sensory nerve conduction, whereas the Lama4 Ϫ/Ϫ and DKO mice exhibit increased sensory nerve action potentials and decreased compound muscle action potentials; x-ray diffraction revealed less mature myelin in the sciatic nerves of the latter than in controls. Ultrastructural analyses revealed changes in the Schwann cell BM in all three mutants, ranging from severe (DKO) to nearly normal (Col15a1 Ϫ/Ϫ ). Collagen XV thus contributes to peripheral nerve maturation and C-fiber formation, and its simultaneous deletion from neural BM zones with laminin ␣4 leads to a DKO phenotype distinct from those of both single knock-outs.

“…This dystrophy is often severe, progressive, and accompanied by neurological deficits in both the peripheral nervous systems and CNSs (Jones et al, 2001). In patients with MDCMD and also in laminin ␣2 knock-out mice, the peripheral nerves display severe dysmyelination, lack of basal lamina, and axon degeneration (Xu et al, 1994;Helbling-Leclerc et al, 1995;Nakagawa et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Impeded Interaction between Schwann Cells and Axons in the Absence of Laminin α4

Wallquist¹,

Plantman²,

Thams³

et al. 2005

The Schwann cell basal lamina (BL) is required for normal myelination. Loss or mutations of BL constituents, such as laminin-2 (␣2␤1␥1), lead to severe neuropathic diseases affecting peripheral nerves. The function of the second known laminin present in Schwann cell BL, laminin-8 (␣4␤1␥1), is so far unknown. Here we show that absence of the laminin ␣4 chain, which distinguishes laminin-8 from laminin-2, leads to a disturbance in radial sorting, impaired myelination, and signs of ataxia and proprioceptive disturbances, whereas the axonal regenerative capacity is not influenced. In vitro studies show poor axon growth of spinal motoneurons on laminin-8, whereas it is extensive on laminin-2. Schwann cells, however, extend longer processes on laminin-8 than on laminin-2, and, in contrast to the interaction with laminin-2, solely use the integrin receptor ␣6␤1 in their interaction with laminin-8. Thus, laminin-2 and laminin-8 have different critical functions in peripheral nerves, mediated by different integrin receptors.