38 THE SCIENTIST | the-scientist.com
ARCHA FOXassociated proteins to bind—that differ-
ent regions of NEAT1 were required for
directing this core-shell organization.^9
NEAT1 is now being finely dissected
to understand how this one RNA can
form a scaffold on which the tiny mem-
braneless organelles can be built.Stress drives paraspeckles
Because NEAT1 is essential for para-
speckle formation, deleting NEAT1 in an
animal makes a paraspeckle knockout. In
2011, Nakagawa established the NEAT1
knockout mouse.^10 However, it showed
no obvious phenotype. This was disap-
pointing to me, and made it hard to jus-
tify continuing to work on paraspeckles.
But as the Hokkaido-based team contin-
ued to scrutinize the mutants, it turned
out that there was a phenotype: some
female knockout mice had reduced fer-
tility.^11 Nakagawa found that paraspeck-
les are abundant in the corpus luteum
that forms in the ovary and emits pro-
gesterone after the release of an ovum.
Loss of NEAT1 prevented the corpus
luteum from forming in some, but not
all, of the knockout females.
That some animals appeared to be
more reliant on paraspeckles than oth-
ers hinted at the possibility that environ-
mental factors are at play when it comes
to paraspeckle function. Sure enough,
my group and others have since found
that various stressors can trigger the for-mation of abundant, larger-than-normal
paraspeckles that sometimes take on an
oblong shape. Paraspeckles seem to be
part of the cell stress response.
The key is NEAT1 transcription:
more NEAT1 RNA means more para-
speckles. A 2018 genome-wide screen
conducted by Lingling Chen at the
Shanghai Institute of Biochemistry and
Cell Biology identified more than 100
factors that increase NEAT1 transcrip-
tion.^12 These include molecular signals
of mitochondrial disturbance, a driver of
many diseases.
As paraspeckle numbers increase
within a cell due to stress, they seques-
ter paraspeckle-associated transcrip-
tion factors such as SFPQ—one of the
first two proteins I discovered to be a
component of paraspeckles, along with
PSPC1—and this changes expression
of the downstream target genes. Large
paraspeckles, which can grow to be up to
2 micrometers long, also sequester spe-
cific mRNAs, stopping them from being
exported from the nucleus and trans-
lated in the cytoplasm. (See illustration
on page 37.) This paraspeckle-drivenTo have discovered
a new cellular
structure and
have watched the
birth of a research
field focused on
understanding
that structure is
an honor and a
privilege.
NUCLEAR SPOTS: A HeLa cell nucleus with
DNA stained blue and paraspeckle markers
in green and red. The large circles within the
nucleus are nucleoli. Scale bar is 5 μm.