Smurfs have “fused” into the asymmetric division of stem cells

Protein & Cell, Feb 2011

Steven Y. Cheng, Ying E. Zhang

A PDF file should load here. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a PDF plug-in installed and enabled in your browser.

Alternatively, you can download the file locally and open with any standalone PDF reader:

https://link.springer.com/content/pdf/10.1007%2Fs13238-011-1005-6.pdf

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 - 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)


This is a preview of a remote PDF: https://link.springer.com/content/pdf/10.1007%2Fs13238-011-1005-6.pdf

Steven Y. Cheng, Ying E. Zhang. Smurfs have “fused” into the asymmetric division of stem cells, Protein & Cell, 2011, pp. 2-4, Volume 2, Issue 1, DOI: 10.1007/s13238-011-1005-6