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The Journal of Neuroscience, October 24, 2007, 27(43):11552-11559; doi:10.1523/JNEUROSCI.5497-06.2007

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Development/Plasticity/Repair
Misexpression of Pou3f1 Results in Peripheral Nerve Hypomyelination and Axonal Loss

Elizabeth J. Ryu,¹ James Y. T. Wang,¹ Nam Le,¹ Robert H. Baloh,^2,3 Jason A. Gustin,¹ Robert E. Schmidt,^1,2 and Jeffrey Milbrandt^1,2,3

¹Department of Pathology and Immunology, ²HOPE Center for Neurological Disorders, and ³Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110

Correspondence should be addressed to Jeffrey Milbrandt, Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, Box 8118, St. Louis, MO 63110. Email: jmilbrandt{at}wustl.edu

Pou3f1/SCIP/Oct-6 is a POU-domain transcription factor that is an important regulator of peripheral nerve myelination by Schwann cells. Pou3f1-deficient mice experience a developmental delay in myelination indicating that transient induction of Pou3f1 is required for normal development of peripheral myelin. The mechanism by which Pou3f1 regulates myelination is unclear, because it can both increase expression of Egr2, a transcription factor that promotes the myelination program, and also repress the promoters of specific myelin genes such as myelin protein zero (MPZ) and myelin basic protein (MBP). Therefore, to investigate the effects of persistent Pou3f1 expression on peripheral nerve myelination, we created a conditional transgenic mouse [condPou3f1:MPZ(Cre)] that constitutively expresses Pou3f1 specifically in peripheral glia. Examination of sciatic nerves from condPou3f1:MPZ(Cre) mice revealed persistent hypomyelination and eventual axonal loss but no evidence of demyelination/remyelination processes or impaired Schwann cell proliferation. Nerves from these mice had normal levels of Egr2 mRNA but decreased levels of MPZ, MBP, and Pmp22 mRNA. Thus, unlike the Pou3f1 null mice, the condPou3f1:MPZ(Cre) mice exhibit persistent hypomyelination, indicating that strict control of Pou3f1 expression is critical to proper myelination. Our findings establish the importance of identifying factor(s) responsible for Pou3f1 downregulation during myelination, because they may play important roles in the development of peripheral neuropathies.

Key words: Pou3f1; Oct-6; SCIP; Egr2; myelination; neuropathy

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Received Dec. 19, 2006; revised July 27, 2007; accepted July 30, 2007.

Correspondence should be addressed to Jeffrey Milbrandt, Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, Box 8118, St. Louis, MO 63110. Email: jmilbrandt{at}wustl.edu

This article has been cited by other articles:

				E. J. Ryu, M. Yang, J. A. Gustin, L.-W. Chang, R. R. Freimuth, R. Nagarajan, and J. Milbrandt Analysis of Peripheral Nerve Expression Profiles Identifies a Novel Myelin Glycoprotein, MP11 J. Neurosci., July 23, 2008; 28(30): 7563 - 7573. [Abstract] [Full Text] [PDF]

				G. M. Mager, R. M. Ward, R. Srinivasan, S.-W. Jang, L. Wrabetz, and J. Svaren Active Gene Repression by the Egr2{middle dot}NAB Complex during Peripheral Nerve Myelination J. Biol. Chem., June 27, 2008; 283(26): 18187 - 18197. [Abstract] [Full Text] [PDF]

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