Egr2 is a transcription factor required for peripheral nerve myelination
in rodents, and mutations in Egr2 are associated with congenital
hypomyelinating neuropathy (CHN) in humans. To further study its
role in myelination, we generated mice harboring a hypomorphic
Egr2 allele (Egr2Lo) that survive for up to 3 weeks postnatally,
a period of active myelination in rodents. These Egr2Lo/Lo mice
provided the opportunity to study the molecular effects of Egr2
deficiency on Schwann cell biology, an analysis that was not possible
previously, because of the perinatal lethality of Egr2-null mice.
Egr2Lo/Lo mice phenocopy CHN, as evidenced by the severe hypomyelination
and increased numbers of proliferating Schwann cells of the peripheral
nerves. Comparison of sciatic nerve gene expression profiles during
development and after crush injury with those of Egr2Lo/Lo Schwann
cells revealed that they are developmentally arrested, with down-regulation
of myelination-related genes and up-regulation of genes associated
with immature and promyelinating Schwann cells. One of the abnormally
elevated genes in Egr2Lo/Lo Schwann cells, Sox2, encodes a transcription
factor that is crucial for maintenance of neural stem cell pluripotency.
Wild-type Schwann cells infected with Sox2 adenovirus or lentivirus
inhibited expression of myelination-associated genes (e.g., myelin
protein zero; Mpz), and failed to myelinate axons in vitro, but
had an enhanced proliferative response to beta-neuregulin. The
characterization of a mouse model of CHN has provided insight
into Schwann cell differentiation and allowed the identification
of Sox2 as a negative regulator of myelination.