The role of human and Drosophila NXF proteins in nuclear mRNA ...

Introduction 30
proteins also differentially affect stripe mRNA stability (Nabel-Rosen et al., 1999; Nabel-
Rosen et al., 2002).
In mammals, an example of regulated mRNA export has recently been reported to
occur during differentiation of the nervous system in mice. The Quaking protein is required
for the maturation of Schwann cells into myelin-forming cells. Different forms of the
Quaking protein are generated by alternative splicing, and the balance between these
different isoforms was shown to control the nuclear export of mbp mRNA. mbp encodes
the "myelin basic protein" and is a major component of myelin (Larocque et al., 2002).
Interestingly, both How and Quaking, belong to a family of RNA-binding proteins called
"signal transduction and activation of RNA" (STAR) family, suggesting that conserved
features found in STAR family members might enable them to regulate nuclear export of
specific mRNAs by a similar mechanism (Larocque et al., 2002; Nabel-Rosen et al., 1999).
These examples illustrate that the tightly controlled export of specific mRNAs can
regulate differentiation. However, the precise molecular mechanisms underlying these
observations e.g. how the nuclear retention of specific mRNAs is achieved, remain to be
investigated.
The role of Crm1 in mRNA export
As described above, Crm1 is essential for the export of U snRNAs, ribosomal
subunits and proteins containing leucine-riche NESs (see 1.1.4, 1.2.2 and 1.2.3). Crm1 is
also involved in the nuclear export of late mRNAs of some retroviruses (e.g. HIV-1), but is
believed to play a rather limited role in the nuclear export of cellular mRNAs (Cullen,
2003)
In yeast, a temperature-sensitive mutant of CRM1 shows a strong nuclear
accumulation of poly(A) + RNA within 15 minutes after the shift to the non-permissive
temperature. This observation first led to the proposal that Crm1p is also an essential and
general export receptor for mRNAs (Stade et al., 1997). However, subsequent experiments
using a S. cerevisiae strain in which Crm1p function can be inhibited with LMB showed
that the nuclear accumulation poly(A) + RNA following LMB treatment occurs with a
significant delay compared to the effect on NES-mediated export. Moreover, LMB
treatment did not result in a marked decrease of protein synthesis, arguing against a role of
Crm1p in general mRNA export (Neville and Rosbash, 1999). This does not exclude a role
for Crm1p in the nuclear export of specific mRNAs.
In vertebrates, the following observations argue against a role for Crm1 in general
mRNA export: first, injection of leucine-rich NES into Xenopus oocytes competes with
U snRNA export, but not with mRNA export (Fischer et al., 1995; Fornerod et al., 1997).
Similarly, high amounts of NES peptide inhibit Crm1-dependent protein export in
mammalian cells, but not bulk mRNA export (Gallouzi and Steitz, 2001). Second, LMB