- Email: [email protected]
Robo-Enabled Tumor Cell Extrusion
Developmental Cell
Previews Bobola, N., and Merabet, S. (2016). Curr. Opin. Genet. Dev. 43, 1–8. Du, H., and Taylor, H.S. (2015). Cold Spring Harb. Perspect. Med. 6, a023002. Leucht, P., Kim, J.B., Amasha, R., James, A.W., Girod, S., and Helms, J.A. (2008). Development 135, 2845–2854.
Morgan, R. (2006). Trends Genet. 22, 67–69. Pineault, K.M., and Wellik, D.M. (2014). Curr. Osteoporos. Rep. 12, 420–427.
Rux, D.R., Song, J.Y., Swinehart, I.T., Pineault, K.M., Schlientz, A.J., Trulik, K.J., Goldstein, S.A., Kozloff, K.M., Lucas, D., and Wellik, D.M. (2016). Dev. Cell 39, this issue, 653–666.
Rezsohazy, R., Saurin, A.J., Maurel-Zaffran, C., and Graba, Y. (2015). Development 142, 1212– 1227.
Zhou, B.O., Yue, R., Murphy, M.M., Peyer, J.G., and Morrison, S.J. (2014). Cell Stem Cell 15, 154–168.
Robo-Enabled Tumor Cell Extrusion Helena E. Richardson1,* and Marta Portela2 1Department
of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia of Molecular, Cellular, and Developmental Neurobiology, Cajal Institute (CSIC), Avenida Doctor Arce, 37, Madrid 28002, Spain *Correspondence: [email protected] http://dx.doi.org/10.1016/j.devcel.2016.12.008 2Department
How aberrant cells are removed from a tissue to prevent tumor formation is a key question in cancer biology. Reporting in this issue of Developmental Cell, Vaughen and Igaki (2016) show that a pathway with an important role in neural guidance also directs extrusion of tumor cells from epithelial tissues. In all multicellular organisms, damaged or mutant cells need to be recognized and removed to maintain tissue function and prevent tumor formation. A surveillance mechanism known as cell competition is important for the detection and elimination of aberrant cells in order to maintain tissue homeostasis (reviewed by Merino et al., 2016). In cell competition, cellular ‘‘fitness,’’ a reflection of translation rates, cellular growth, mitogenic signaling, and cell polarity, is monitored within a tissue, and cells with lower fitness (losers) due to genetic or physical damage are recognized and actively eliminated from the tissue. Cell competition was originally discovered in the vinegar fly model organism, Drosophila melanogaster, but is now also known to occur in mammalian systems (reviewed by Merino et al., 2016). Studies in Drosophila have revealed that the mechanism by which loser cells, with reduced translation, cellular growth, or mitogenic signaling, are recognized depends upon cell-surface receptors and innate immune system signaling, which result in the induction of caspase-dependent cell death and extrusion from the epithelium (reviewed by Merino et al., 2016). In 95% of cases, extrusion occurs basally and the dying cells are engulfed by macrophage-like cells (hemocytes), while in 5% of cases the loser cells are en-
gulfed by their epithelial neighbors in the apical region (Casas-Tinto´ et al., 2015). Cells with aberrant cell polarity or morphology within an epithelium appear to require different mechanisms to elicit their removal and engulfment (Ohsawa et al., 2011; reviewed by Pastor-Pareja and Xu, 2013). Disruption of cell polarity, as occurs with loss-of-function mutations in the apicobasal cell polarity regulator Scribbled (Scrib) leads to elevation of the Jun kinase (JNK) signaling pathway, which in a heterogenic epithelium triggers caspase-mediated cell death of the scrib mutant cells (reviewed by Pastor-Pareja and Xu, 2013). However, elevated JNK signaling in polarity-impaired cells also regulates the expression of differentiation and signaling pathway genes (Bunker et al., 2015), which might impact cell competition, extrusion, and elimination processes. In this issue of Developmental Cell, Vaughen and Igaki (2016) have discovered targets of JNK signaling that are important in the extrusion mechanism of scrib mutant cells from a heterogenic epithelium in Drosophila. Vaughen and Igaki identified Enabled/ VASP (Ena), a regulator of actin nucleation, in a genetic screen for genes required for scrib mutant cell elimination in the Drosophila eye epithelium. Ena is known to be regulated by the Slit ligand and
Roundabout (Robo) receptor, which play a repulsive role in neural pathfinding. Consistent with the conservation of this regulatory mechanism, Vaughen and Igaki also found that Slit and one of the three Drosophila Robo receptors, Robo2, were required for the elimination of scrib mutant cells. Also in line with the role of Slit-Robo2Ena in cell-cell repulsion, Vaughen and Igaki (2016) observed that this pathway was involved in the extrusion of scrib mutant cells from the epithelium, predominantly basally, where the cells rapidly underwent apoptosis. When Slit-Robo2-Ena signaling was disrupted, scrib mutant cells remained in the epithelial layer and overproliferated to form tumors. Moreover, they showed that slit, robo2, and ena are targets of the JNK signaling pathway and identified binding sites for the JNK-regulated transcription factor AP1 (Jun/Fos), in the intronic regions of these genes. Vaughen and Igaki (2016) also found that JNK signaling was important for the basal extrusion of scrib mutant cells and that Slit-Robo2-Ena signaling was required downstream of JNK for scrib mutant cell extrusion. Interestingly, they also found that Slit-Robo2-Ena signaling resulted in elevated F-actin polymerization and JNK activation, triggering a positive feedback loop enhancing slit, robo2, and ena gene expression. Altogether, their results
Developmental Cell 39, December 19, 2016 ª 2016 Elsevier Inc. 629
Developmental Cell
Previews
Figure 1. Slit-Robo2-Ena Signaling Dictates Tumor Cell Extrusion and Death or Survival (A) Slit-Robo2-Ena signaling drives scrib mutant cell extrusion from the epithelium (Disc Proper), mainly basally, where TNF (Egr)-JNK signaling from hemocytes results in their elimination. JNK signaling elevates Slit-Robo2-Ena expression, which in turn leads to elevated JNK activity through downregulation of E-cadherin and effects on the actin cytoskeleton, thereby promoting tumor cells extrusion from the epithelium. It remains to be determined whether Ena interactors (Abl, Trio, and Fra) might also be involved. (B) Over-activation of Slit-Robo2-Ena signaling results in a hyper-extrusion phenotype, in which cells are extruded basally and die or apically into the lumen where they survive and proliferate, perhaps by exploiting endogenous mitogenic pathways, such as Jak-Stat signaling.
indicate that the Slit-Robo2-Ena signaling pathway is critical for driving basal extrusion of scrib mutant cells, where they undergo apoptosis. Intriguingly, the authors also found that over-activation of Slit-Robo2-Ena signaling results in hyperextrusion of cells, both basally, where they die, and apically into the lumen between the eye epithelium and the peripo-
dial membrane epithelium, where they proliferate to form tumors. Mechanistically, Vaughen and Igaki (2016) demonstrated that the Slit-Robo2-Ena signaling pathway promoted scrib mutant cell extrusion by downregulating the adherens junction protein E-cadherin (Shotgun). Additionally, they observed that Robo2 expression induced the accumulation of myosin
630 Developmental Cell 39, December 19, 2016
regulatory light chain (Spaghetti Squash, Sqh). Given the requirement of E-cadherin for cell-cell adhesion and the importance of actinomyosin activity for cell morphology changes, the Slit-Robo2Ena-induced reduction of E-cadherin and elevation of Sqh levels, together with the known effects of Ena on actin nucleation, would then drive scrib mutant cell extrusion (Figure 1). The findings from the Vaughen and Igaki (2016) study evoke several interesting questions concerning cell competition and the consequences of cell extrusion. First, why does basal versus apical extrusion results in opposing effects on the fate of scrib mutant cells? A recent study of the extrusion of polarity-impaired cells in the wing epithelium might shed light on this phenomenon (Tamori et al., 2016). In that study, the authors found ‘‘hotspots’’ where cells were apically extruded and survived due to exploitation of endogenous Janus kinase (Jak)/Stat signaling and ‘‘cold spots’’ where basal cell extrusion resulted in apoptosis. Cell death most likely occurs basally, since hemocytes are recruited to the basal side of epithelia and secrete the tumor necrosis factor (TNF) ligand Eiger (Egr) to activate TNF-JNK signaling in the extruding cells (reviewed by Pastor-Pareja and Xu, 2013) (Figure 1). Second, since other cytoskeletal regulators, such as the Abl tyrosine kinase, the GTPase Trio, and another guidance receptor, Frazzled (Neogenin/DCC Netrin 1 receptor), interact with Ena in neural guidance, this raises the question of whether these molecules are also involved in extrusion of scrib mutant cells (Figure 1). Third, is this mechanism required for other types of cell competition? Lastly, how does the Slit-Robo2-Ena pathway integrate with other pathways, such as Jak-Stat and Hippo signaling, which are involved in scrib mutant cell elimination in Drosophila epithelial tissues (Bunker et al., 2015; Pastor-Pareja and Xu, 2013; Schroeder et al., 2013), or pathways involved in the apical engulfment of scrib mutant cells (Ohsawa et al., 2011)? The answers to these questions will provide greater insight into the regulation and general importance of the Slit-Robo2-Ena pathway in maintaining tissue integrity. Importantly, the Vaughen and Igaki (2016) study has also revealed parallels with mammalian cell systems that have
Developmental Cell
Previews implications for the understanding of human tumorigenesis. In mammalian cell monolayers, inducible knockdown of scrib in individual cells within a wild-type epithelium also results in extrusion of the mutant cells, and this is dependent on the stressinduced JNK-related kinase p38 (Norman et al., 2012). Whether the Slit-Robo-Ena pathway is also induced by p38 and required downstream of p38 signaling for scrib mutant cell extrusion is the obvious next line of inquiry. Similar to the findings of Vaughen and Igaki (2016), an important role for E-cadherin was also discovered for mutant cell extrusion from mammalian cell monolayers; in mixed cultures of Rastransformed (RasV12) cells, which are apically or basally extruded, E-cadherin was required in the normal cells surrounding RasV12 cells to promote apical extrusion and reduce basal extrusion of the transformed cells (reviewed by Merino
et al., 2016). Thus, the relative level of E-cadherin between mutant and normal cells might be a conserved mechanism for mutant cell extrusion from epithelial tissues in flies and mammalian cells. Given that aberrant Robo signaling is now recognized as an important cancerassociated pathway in humans, where it can affect several cancer hallmarks (Blockus and Che´dotal, 2016), the findings of Vaughen and Igaki (2016) provide new ways forward in interrogating the function of Robo signaling in human cancer development.
Casas-Tinto´, S., Lolo, F.N., and Moreno, E. (2015). Nat. Commun. 6, 10022. Merino, M.M., Levayer, R., and Moreno, E. (2016). Trends Cell Biol. 26, 776–788. Norman, M., Wisniewska, K.A., Lawrenson, K., Garcia-Miranda, P., Tada, M., Kajita, M., Mano, H., Ishikawa, S., Ikegawa, M., Shimada, T., and Fujita, Y. (2012). J. Cell Sci. 125, 59–66. Ohsawa, S., Sugimura, K., Takino, K., Xu, T., Miyawaki, A., and Igaki, T. (2011). Dev. Cell 20, 315–328. Pastor-Pareja, J.C., and Xu, T. (2013). Annu. Rev. Genet. 47, 51–74. Schroeder, M.C., Chen, C.L., Gajewski, K., and Halder, G. (2013). Oncogene 32, 4471–4479.
REFERENCES Blockus, H., and Che´dotal, A. (2016). Development 143, 3037–3044. Bunker, B.D., Nellimoottil, T.T., Boileau, R.M., Classen, A.K., and Bilder, D. (2015). eLife 4, e03189.
Tamori, Y., Suzuki, E., and Deng, W.M. (2016). PLoS Biol. 14, e1002537. Vaughen, J., and Igaki, T. (2016). Dev. Cell 39, this issue, 683–695.
Germ Cells Get by with a Little Cannibalistic Help from Their Friends Shefali Krishna1,2 and Michael Overholtzer1,2,* 1Cell
Biology Program V. Gerstner Jr. Graduate School of Biomedical Sciences Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.devcel.2016.12.003 2Louis
During development, primordial germ cells (PGCs) navigate a complex journey to generate the germline. In a recent paper in Nature Cell Biology, Nance and colleagues (Abdu et al., 2016) have discovered an unexpected step along the way: PGCs get cut in half by endodermal cells. Primordial germ cells (PGCs) and endodermal cells are known to associate closely during development. In C. elegans and Drosophila, endodermal cells have been shown to bind to PGCs and are responsible for pulling PGCs inward into the embryo during gastrulation (Chihara and Nance, 2012). Once positioned, PGCs in numerous species maintain a close association with the endoderm as they await their long migration, a greater than 2 day journey in mammalian development that takes them from the hindgut through the dorsal body wall and on to the genital ridge, where
they differentiate into gametes (Molyneaux et al., 2001). In C. elegans, it was previously observed that large pieces of individual PGCs called lobes protrude into neighboring endodermal cells during development (Sulston et al., 1983), but it was not known what these structures were or how or why they formed. Now in a new study by Abdu et al. (2016), Nance and colleagues take a closer look at PGC lobes and make an important discovery. Using time-lapse microscopy to image C. elegans embryos, the authors found that PGCs indeed extended large lobes
into neighboring endodermal cells at the 1(1/2)-fold stage of development after gastrulation. The observed PGC lobes were of considerable volume—about 232 mm3 on average, slightly more than the remaining volume of the cell body. While the formation of these large lobes occurred cell autonomously, as they were formed even by isolated PGCs, neighboring endodermal cells were found to engulf and degrade lobes within intact embryos, suggesting an active, cannibalistic process that dramatically remodels PGC size during development (Figure 1).
Developmental Cell 39, December 19, 2016 ª 2016 Elsevier Inc. 631
Previews Bobola, N., and Merabet, S. (2016). Curr. Opin. Genet. Dev. 43, 1–8. Du, H., and Taylor, H.S. (2015). Cold Spring Harb. Perspect. Med. 6, a023002. Leucht, P., Kim, J.B., Amasha, R., James, A.W., Girod, S., and Helms, J.A. (2008). Development 135, 2845–2854.
Morgan, R. (2006). Trends Genet. 22, 67–69. Pineault, K.M., and Wellik, D.M. (2014). Curr. Osteoporos. Rep. 12, 420–427.
Rux, D.R., Song, J.Y., Swinehart, I.T., Pineault, K.M., Schlientz, A.J., Trulik, K.J., Goldstein, S.A., Kozloff, K.M., Lucas, D., and Wellik, D.M. (2016). Dev. Cell 39, this issue, 653–666.
Rezsohazy, R., Saurin, A.J., Maurel-Zaffran, C., and Graba, Y. (2015). Development 142, 1212– 1227.
Zhou, B.O., Yue, R., Murphy, M.M., Peyer, J.G., and Morrison, S.J. (2014). Cell Stem Cell 15, 154–168.
Robo-Enabled Tumor Cell Extrusion Helena E. Richardson1,* and Marta Portela2 1Department
of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia of Molecular, Cellular, and Developmental Neurobiology, Cajal Institute (CSIC), Avenida Doctor Arce, 37, Madrid 28002, Spain *Correspondence: [email protected] http://dx.doi.org/10.1016/j.devcel.2016.12.008 2Department
How aberrant cells are removed from a tissue to prevent tumor formation is a key question in cancer biology. Reporting in this issue of Developmental Cell, Vaughen and Igaki (2016) show that a pathway with an important role in neural guidance also directs extrusion of tumor cells from epithelial tissues. In all multicellular organisms, damaged or mutant cells need to be recognized and removed to maintain tissue function and prevent tumor formation. A surveillance mechanism known as cell competition is important for the detection and elimination of aberrant cells in order to maintain tissue homeostasis (reviewed by Merino et al., 2016). In cell competition, cellular ‘‘fitness,’’ a reflection of translation rates, cellular growth, mitogenic signaling, and cell polarity, is monitored within a tissue, and cells with lower fitness (losers) due to genetic or physical damage are recognized and actively eliminated from the tissue. Cell competition was originally discovered in the vinegar fly model organism, Drosophila melanogaster, but is now also known to occur in mammalian systems (reviewed by Merino et al., 2016). Studies in Drosophila have revealed that the mechanism by which loser cells, with reduced translation, cellular growth, or mitogenic signaling, are recognized depends upon cell-surface receptors and innate immune system signaling, which result in the induction of caspase-dependent cell death and extrusion from the epithelium (reviewed by Merino et al., 2016). In 95% of cases, extrusion occurs basally and the dying cells are engulfed by macrophage-like cells (hemocytes), while in 5% of cases the loser cells are en-
gulfed by their epithelial neighbors in the apical region (Casas-Tinto´ et al., 2015). Cells with aberrant cell polarity or morphology within an epithelium appear to require different mechanisms to elicit their removal and engulfment (Ohsawa et al., 2011; reviewed by Pastor-Pareja and Xu, 2013). Disruption of cell polarity, as occurs with loss-of-function mutations in the apicobasal cell polarity regulator Scribbled (Scrib) leads to elevation of the Jun kinase (JNK) signaling pathway, which in a heterogenic epithelium triggers caspase-mediated cell death of the scrib mutant cells (reviewed by Pastor-Pareja and Xu, 2013). However, elevated JNK signaling in polarity-impaired cells also regulates the expression of differentiation and signaling pathway genes (Bunker et al., 2015), which might impact cell competition, extrusion, and elimination processes. In this issue of Developmental Cell, Vaughen and Igaki (2016) have discovered targets of JNK signaling that are important in the extrusion mechanism of scrib mutant cells from a heterogenic epithelium in Drosophila. Vaughen and Igaki identified Enabled/ VASP (Ena), a regulator of actin nucleation, in a genetic screen for genes required for scrib mutant cell elimination in the Drosophila eye epithelium. Ena is known to be regulated by the Slit ligand and
Roundabout (Robo) receptor, which play a repulsive role in neural pathfinding. Consistent with the conservation of this regulatory mechanism, Vaughen and Igaki also found that Slit and one of the three Drosophila Robo receptors, Robo2, were required for the elimination of scrib mutant cells. Also in line with the role of Slit-Robo2Ena in cell-cell repulsion, Vaughen and Igaki (2016) observed that this pathway was involved in the extrusion of scrib mutant cells from the epithelium, predominantly basally, where the cells rapidly underwent apoptosis. When Slit-Robo2-Ena signaling was disrupted, scrib mutant cells remained in the epithelial layer and overproliferated to form tumors. Moreover, they showed that slit, robo2, and ena are targets of the JNK signaling pathway and identified binding sites for the JNK-regulated transcription factor AP1 (Jun/Fos), in the intronic regions of these genes. Vaughen and Igaki (2016) also found that JNK signaling was important for the basal extrusion of scrib mutant cells and that Slit-Robo2-Ena signaling was required downstream of JNK for scrib mutant cell extrusion. Interestingly, they also found that Slit-Robo2-Ena signaling resulted in elevated F-actin polymerization and JNK activation, triggering a positive feedback loop enhancing slit, robo2, and ena gene expression. Altogether, their results
Developmental Cell 39, December 19, 2016 ª 2016 Elsevier Inc. 629
Developmental Cell
Previews
Figure 1. Slit-Robo2-Ena Signaling Dictates Tumor Cell Extrusion and Death or Survival (A) Slit-Robo2-Ena signaling drives scrib mutant cell extrusion from the epithelium (Disc Proper), mainly basally, where TNF (Egr)-JNK signaling from hemocytes results in their elimination. JNK signaling elevates Slit-Robo2-Ena expression, which in turn leads to elevated JNK activity through downregulation of E-cadherin and effects on the actin cytoskeleton, thereby promoting tumor cells extrusion from the epithelium. It remains to be determined whether Ena interactors (Abl, Trio, and Fra) might also be involved. (B) Over-activation of Slit-Robo2-Ena signaling results in a hyper-extrusion phenotype, in which cells are extruded basally and die or apically into the lumen where they survive and proliferate, perhaps by exploiting endogenous mitogenic pathways, such as Jak-Stat signaling.
indicate that the Slit-Robo2-Ena signaling pathway is critical for driving basal extrusion of scrib mutant cells, where they undergo apoptosis. Intriguingly, the authors also found that over-activation of Slit-Robo2-Ena signaling results in hyperextrusion of cells, both basally, where they die, and apically into the lumen between the eye epithelium and the peripo-
dial membrane epithelium, where they proliferate to form tumors. Mechanistically, Vaughen and Igaki (2016) demonstrated that the Slit-Robo2-Ena signaling pathway promoted scrib mutant cell extrusion by downregulating the adherens junction protein E-cadherin (Shotgun). Additionally, they observed that Robo2 expression induced the accumulation of myosin
630 Developmental Cell 39, December 19, 2016
regulatory light chain (Spaghetti Squash, Sqh). Given the requirement of E-cadherin for cell-cell adhesion and the importance of actinomyosin activity for cell morphology changes, the Slit-Robo2Ena-induced reduction of E-cadherin and elevation of Sqh levels, together with the known effects of Ena on actin nucleation, would then drive scrib mutant cell extrusion (Figure 1). The findings from the Vaughen and Igaki (2016) study evoke several interesting questions concerning cell competition and the consequences of cell extrusion. First, why does basal versus apical extrusion results in opposing effects on the fate of scrib mutant cells? A recent study of the extrusion of polarity-impaired cells in the wing epithelium might shed light on this phenomenon (Tamori et al., 2016). In that study, the authors found ‘‘hotspots’’ where cells were apically extruded and survived due to exploitation of endogenous Janus kinase (Jak)/Stat signaling and ‘‘cold spots’’ where basal cell extrusion resulted in apoptosis. Cell death most likely occurs basally, since hemocytes are recruited to the basal side of epithelia and secrete the tumor necrosis factor (TNF) ligand Eiger (Egr) to activate TNF-JNK signaling in the extruding cells (reviewed by Pastor-Pareja and Xu, 2013) (Figure 1). Second, since other cytoskeletal regulators, such as the Abl tyrosine kinase, the GTPase Trio, and another guidance receptor, Frazzled (Neogenin/DCC Netrin 1 receptor), interact with Ena in neural guidance, this raises the question of whether these molecules are also involved in extrusion of scrib mutant cells (Figure 1). Third, is this mechanism required for other types of cell competition? Lastly, how does the Slit-Robo2-Ena pathway integrate with other pathways, such as Jak-Stat and Hippo signaling, which are involved in scrib mutant cell elimination in Drosophila epithelial tissues (Bunker et al., 2015; Pastor-Pareja and Xu, 2013; Schroeder et al., 2013), or pathways involved in the apical engulfment of scrib mutant cells (Ohsawa et al., 2011)? The answers to these questions will provide greater insight into the regulation and general importance of the Slit-Robo2-Ena pathway in maintaining tissue integrity. Importantly, the Vaughen and Igaki (2016) study has also revealed parallels with mammalian cell systems that have
Developmental Cell
Previews implications for the understanding of human tumorigenesis. In mammalian cell monolayers, inducible knockdown of scrib in individual cells within a wild-type epithelium also results in extrusion of the mutant cells, and this is dependent on the stressinduced JNK-related kinase p38 (Norman et al., 2012). Whether the Slit-Robo-Ena pathway is also induced by p38 and required downstream of p38 signaling for scrib mutant cell extrusion is the obvious next line of inquiry. Similar to the findings of Vaughen and Igaki (2016), an important role for E-cadherin was also discovered for mutant cell extrusion from mammalian cell monolayers; in mixed cultures of Rastransformed (RasV12) cells, which are apically or basally extruded, E-cadherin was required in the normal cells surrounding RasV12 cells to promote apical extrusion and reduce basal extrusion of the transformed cells (reviewed by Merino
et al., 2016). Thus, the relative level of E-cadherin between mutant and normal cells might be a conserved mechanism for mutant cell extrusion from epithelial tissues in flies and mammalian cells. Given that aberrant Robo signaling is now recognized as an important cancerassociated pathway in humans, where it can affect several cancer hallmarks (Blockus and Che´dotal, 2016), the findings of Vaughen and Igaki (2016) provide new ways forward in interrogating the function of Robo signaling in human cancer development.
Casas-Tinto´, S., Lolo, F.N., and Moreno, E. (2015). Nat. Commun. 6, 10022. Merino, M.M., Levayer, R., and Moreno, E. (2016). Trends Cell Biol. 26, 776–788. Norman, M., Wisniewska, K.A., Lawrenson, K., Garcia-Miranda, P., Tada, M., Kajita, M., Mano, H., Ishikawa, S., Ikegawa, M., Shimada, T., and Fujita, Y. (2012). J. Cell Sci. 125, 59–66. Ohsawa, S., Sugimura, K., Takino, K., Xu, T., Miyawaki, A., and Igaki, T. (2011). Dev. Cell 20, 315–328. Pastor-Pareja, J.C., and Xu, T. (2013). Annu. Rev. Genet. 47, 51–74. Schroeder, M.C., Chen, C.L., Gajewski, K., and Halder, G. (2013). Oncogene 32, 4471–4479.
REFERENCES Blockus, H., and Che´dotal, A. (2016). Development 143, 3037–3044. Bunker, B.D., Nellimoottil, T.T., Boileau, R.M., Classen, A.K., and Bilder, D. (2015). eLife 4, e03189.
Tamori, Y., Suzuki, E., and Deng, W.M. (2016). PLoS Biol. 14, e1002537. Vaughen, J., and Igaki, T. (2016). Dev. Cell 39, this issue, 683–695.
Germ Cells Get by with a Little Cannibalistic Help from Their Friends Shefali Krishna1,2 and Michael Overholtzer1,2,* 1Cell
Biology Program V. Gerstner Jr. Graduate School of Biomedical Sciences Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.devcel.2016.12.003 2Louis
During development, primordial germ cells (PGCs) navigate a complex journey to generate the germline. In a recent paper in Nature Cell Biology, Nance and colleagues (Abdu et al., 2016) have discovered an unexpected step along the way: PGCs get cut in half by endodermal cells. Primordial germ cells (PGCs) and endodermal cells are known to associate closely during development. In C. elegans and Drosophila, endodermal cells have been shown to bind to PGCs and are responsible for pulling PGCs inward into the embryo during gastrulation (Chihara and Nance, 2012). Once positioned, PGCs in numerous species maintain a close association with the endoderm as they await their long migration, a greater than 2 day journey in mammalian development that takes them from the hindgut through the dorsal body wall and on to the genital ridge, where
they differentiate into gametes (Molyneaux et al., 2001). In C. elegans, it was previously observed that large pieces of individual PGCs called lobes protrude into neighboring endodermal cells during development (Sulston et al., 1983), but it was not known what these structures were or how or why they formed. Now in a new study by Abdu et al. (2016), Nance and colleagues take a closer look at PGC lobes and make an important discovery. Using time-lapse microscopy to image C. elegans embryos, the authors found that PGCs indeed extended large lobes
into neighboring endodermal cells at the 1(1/2)-fold stage of development after gastrulation. The observed PGC lobes were of considerable volume—about 232 mm3 on average, slightly more than the remaining volume of the cell body. While the formation of these large lobes occurred cell autonomously, as they were formed even by isolated PGCs, neighboring endodermal cells were found to engulf and degrade lobes within intact embryos, suggesting an active, cannibalistic process that dramatically remodels PGC size during development (Figure 1).
Developmental Cell 39, December 19, 2016 ª 2016 Elsevier Inc. 631