Smurfs have “fused” into the asymmetric division of stem cells
Protein Cell
Smurfs have “fused” into the asymmetric division of stem cells
Steven Y. Cheng 1
Ying E. Zhang 0
0 Laboratory of Cellular and Molecular Biology, National Cancer Institute, National Institutes of Health , 37 Convent Drive, Bethesda, MD 20892 , USA
1 Department of Developmental Genetics, Center for Regenerative Medicine, Nanjing Medical University , 140 Hanzhong Road, Nanjing 210029 , China
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The asymmetric cell division is the way in which a stem cell
divides into one daughter stem cell and one differentiated
daughter cell. This process is one of the key principles of
developmental biology that ensures the perpetual supply of
stem cells while allowing a particular cell lineage to be
populated. During Drosophila oogenesis, the fate of the
daughter stem cell produced from the asymmetric division of
germline stem cells (GSCs) is specified by Decapentaplegic
(Dpp), but the other daughter cell has almost equal access to
the Dpp signal. How Dpp signaling is inactivated in the
differentiated daughter cell has been a deep mystery until a
recent study, led by Dahua Chen of the Institute of Zoology,
China
(Xia et al., 2010)
, showed that the Dpp receptor, Thick
vein (Tkv), is degraded specifically in the differentiated
daughter cell by an HECT-domain ubiquitin E3 ligase,
Smurf, in conjunction with a serine-threonine kinase Fused
(Fu). This finding is as much revealing as it is surprising,
because up until now Fu is considered a core member of the
Hedgehog signaling pathway. Whether Fu serendipitously
steps onto the turf of Dpp signaling or its regulation of Tkv
degradation foretells an elaborate coordination between two
important cell-cell communication systems will surely be a hot
button issue for future studies.
The Drosophila ovary is a fascinating organ for studying
regulation of stem cell fate decisions by surrounding stromal
cells (Fig. 1). Each adult ovary is composed of about 15 linear
strings of follicles called ovarioles. Follicles are formed in the
most anterior part of the ovariole known as germarium,
mature progressively toward the posterior, and eventually bud
off. The germarium can be morphologically divided into 3
distinctive regions; region 1 contains 2–3 GSCs residing in the
anterior part of the germarium encasement. A stack of
terminal filament cells (TF) at the anterior apex of the
germarium wall and a single ring of adjoining cap cells
(CPC) form a stromal niche, which instructs the contacting
daughter cell produced from the asymmetric division of GSCs
to maintain the stem cell fate. The other daughter cell, which
is positioned posterior to the daughter stem cell and in contact
with the cap cell and the inner germarium sheath cell (IGC),
becomes the differentiated cystoblast (CB). Each cystoblast
undergoes precisely 4 rounds of mitosis with incomplete
cytokinesis to give rise to 16 interconnected cystocytes in
region 2a. This 16-cell syncytium is enveloped by somatic
prefollicular cells in region 2b, and is joined by additional
somatic cells as the maturing follicle prepares to bud off in
region 3. Only one of the 16 cystocytes will become the
oocyte, while the rests form the nurse cells. The stromal niche
surrounding GSCs secretes many morphogenic signals
Smurfs “fused” into the asymmetric division of stem cells
including Hedgehog, Wingless, and Dpp, each with a different
role. Over 10 years ago, Ting Xie and Allan C. Spradling at the
Carnegie Institute of Washington showed that ectopic
expression of Dpp in the ovary resulted in the germarium
filled with large germline cells, a phenotype reminiscent of
what was shown in bag of marbles (bam). Bam is a stem cell
differentiation factor that is specifically expressed in CBs but
not in GSCs. The large germline cells induced by Dpp were
actually germline tumors, so this observation established the
crucial role of Dpp in specifying the germline stem cell fate by
suppressing Bam expression
(Xie and Spradling, 1998)
.
However, why does not the posterior daughter cell that is
destined to be cystoblast respond to Dpp?
To address that question, Chen’s group decided to turn on
Dpp signaling in CBs autonomously by ectopic expression of
a constitutively activated form of Dpp receptor, Tkv(ca), from a
bam promoter using the binary UAS (Upstream Activating
Sequence) system. To their dismay, this approach permitted
the germline to develop normally. After checking a few
controls to make sure that the bam promoter was active, they
found that Tkv(ca) was not expressed in CBs, and instead it
was degraded. To investigate what caused Tkv(ca)
degradation, they conducted mass spectrometry analysis and
identified Fu as one of interacting proteins. It appears that
the cytoplasmic domain of Tkv can specifically bind to either
the N- or the C-terminus of Fu. Chen’s group demonstrated
that in fu mutants as well as in flies in which fu was inactivated
by a microRNA-based RNAi strategy, the germarium
accumulated tumorous GSC-like cells, much like the effec (...truncated)