Abstract
Myelin is required for proper nervous system function. Schwann cells in developing nerves depend on extrinsic signals from the axon and from the extracellular matrix to first sort and ensheathe a single axon and then myelinate it. Neuregulin 1 type III (Nrg1III) and laminin α2β1γ1 (Lm211) are the key axonal and matrix signals, respectively, but how their signaling is integrated and if each molecule controls both axonal sorting and myelination is unclear. Here, we use a series of epistasis experiments to show that Lm211 modulates neuregulin signaling to ensure the correct timing and amount of myelination. Lm211 can inhibit Nrg1III by limiting protein kinase A (PKA) activation, which is required to initiate myelination. We provide evidence that excessive PKA activation amplifies promyelinating signals downstream of neuregulin, including direct activation of the neuregulin receptor ErbB2 and its effector Grb2-Associated Binder-1 (Gab1), thereby elevating the expression of the key transcription factors Oct6 and early growth response protein 2 (Egr2). The inhibitory effect of Lm211 is seen only in fibers of small caliber. These data may explain why hereditary neuropathies associated with decreased laminin function are characterized by focally thick and redundant myelin.
Highlights
Myelin is essential for rapid impulse propagation and the proper function of the nervous system
In the peripheral nervous system, myelin is produced by Schwann cells
While this has been interpreted as laminin α2β1γ1 (Lm211) promoting wrapping and myelination, Lm211 may instead only enable Schwann cell (SC) to arrive into a 1:1 relationship with axons, which leads to myelination upon neuregulin 1 (Nrg1) activation independently of laminins
Summary
Myelin is essential for rapid impulse propagation and the proper function of the nervous system. Schwann cells (SCs) form myelin in peripheral nerves in 2 subsequent steps, radial sorting of axons and myelination. Immature SCs segregate axons with a diameter larger than 1 μm to the edge of embryonic axon bundles and acquire a 1:1 relationship with these axons and differentiate into promyelinating SCs. Immature SCs express the transcription factor Oct (Pou3f1) that is later downregulated [1,2], while promyelinating SCs express the transcription factor early growth response protein 2 (Egr or Krox20) that is necessary to transition into wrapping and myelination [3]. A signaling pathway consisting of 30-50cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA), possibly via regulation of Nfkb and Oct, is required to achieve full Egr activation and myelination [2,4,5,6,7]. Groups of small axons that are not radially sorted into a 1:1 ratio remain ensheathed by nonmyelinating SCs, which organize the associated axons into a Remak bundle
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