Abstract
Mutations that disrupt Egr2 transcriptional activity cause severe demyelinating peripheral neuropathies. Here we provide evidence that Nab1 and Nab2 proteins are critical transcriptional modulators of Egr2 in myelinating Schwann cells. Like Egr2, these proteins are essential for Schwann cell differentiation into the myelinating state. Mice lacking both Nab1 and Nab2 show severe congenital hypomyelination of peripheral nerves, with Schwann cell development arresting at the promyelinating stage, despite elevated Egr2 expression. As observed for Egr2, Nab proteins are necessary for Schwann cells to exit the cell cycle, downregulate suppressed cAMP-inducible protein (SCIP) expression and upregulate expression of critical myelination genes. The mRNA expression signature of Schwann cells deficient in both Nab1 and Nab2 is highly similar to that of Egr2-deficient Schwann cells, further indicating that the Egr2/Nab protein complex is a key regulator of the Schwann cell myelination program and that disruption of this transcriptional complex is likely to result in Schwann cell dysfunction in patients with Egr2 mutations.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Alleles
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Animals
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Cartilage / physiopathology
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Cell Differentiation
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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DNA-Binding Proteins / physiology
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Early Growth Response Protein 2
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Gene Expression Profiling
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Gene Expression Regulation / physiology
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Humans
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Hyperplasia
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Male
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Mice
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Mice, Knockout
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Muscle Spindles / pathology
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Myelin Sheath / pathology
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Myelin Sheath / physiology*
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Neoplasm Proteins / deficiency
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Neoplasm Proteins / metabolism
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Neoplasm Proteins / physiology*
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Osteogenesis
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Peripheral Nervous System / metabolism
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Peripheral Nervous System / physiology*
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Phenotype
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Repressor Proteins / metabolism
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Repressor Proteins / physiology*
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Rhombencephalon / pathology
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Schwann Cells / metabolism
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Schwann Cells / pathology
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Schwann Cells / physiology
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Sciatic Nerve / pathology
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Skin / pathology
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Testis / pathology
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transcription Factors / physiology
Substances
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DNA-Binding Proteins
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EGR2 protein, human
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Early Growth Response Protein 2
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Egr2 protein, mouse
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Nab1 protein, mouse
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Nab2 protein, mouse
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Neoplasm Proteins
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Repressor Proteins
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Transcription Factors