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Of Russian dolls and river blindness
250
News & Comment
TRENDS in Cell Biology Vol.12 No.6 June 2002
Journal Club
Netrin and the GTPases Guidance molecules such as the netrins, the semaphorins or ephrins are key regulators of development of the central nervous system. These signals are thought to modulate neurite extension by providing instructive cues that act as attractants or repellents in different cell types. Current research focuses on the identification of the intracellular pathway leading to the regulation of the actin cytoskeleton required for such adapted cell behaviors. The small GTPases of the Rho family (RhoA, Rac1 and Cdc42) are largely involved in the transduction cascade ensuring the formation of filopodia (Cdc42) and lamellipodia (Rac1) of elongating growth cones. Therefore, it was logical to investigate recruitment of small GTPases during axonal guidance in response to semaphorins or ephrins. In this way, the interactions between Netrin-1 (a bifunctional guidance signal), DCC (‘deleted in colorectal cancer’, the receptor for Netrin-1) and Rho family members
Rac1 and Cdc42 have recently been explored [1,2]. Sherakabi and Kennedy [1] analyzed the consequence of inactivation of GTPases in different cell lines and growth cones following netrin-1-dependent filopodia extension. In their model, induced expression of DCC triggered an increase in the number of filopodia and cell-surface area when cells were exposed to netrin-1. Coexpression of DCC with dominant-negative forms of Cdc42 and Rac1 blocked upregulation of filopodia and augmentation of cell-surface area, respectively. Activation of these GTPases by netrin-1 was verified by detecting the amount of GTP-bound Cdc42 and Rac1 by western blot analysis. Interestingly, the authors showed that DCC was able to activate Cdc42 or Rac1 independently. A second study conducted by the group of Lamarche-Vane confirms the role of Cdc42 and Rac1 during neurite
extension and provides evidence for the requirement for downregulation of RhoA and Rho-kinase [2]. Future studies will have to elucidate the molecular nature of the protein(s) coupling DCC to GTPases. Because DCC is considered to be a tumor-suppressor gene, alongside the fundamental interest generated by elucidating the signaling pathway stemming from its activation, these studies could well shed light on the mechanisms controlling tumor progression. 1 Sherakabi, M. and Kennedy, T.E. (2002) The Netrin-1 receptor DCC promotes filopodia formation and cell spreading by activating Cdc42 and Rac1. Mol. Cell. Neurosci. 19, 1–17 2 Li, X. et al. Rac1 and Cdc42 but not RhoA or Rhokinase activities are required for neurite outgrowth induced by the Netrin-1 DCC (deleted in colorectal cancer) in N1E-115 neuroblastoma cells. J. Biol. Chem. (in press)
Dominique Bagnard [email protected]
Of Russian dolls and river blindness For those fortunate enough to live in the developed world, encounters with parasitic worms are usually more embarrassing than life-threatening, but, in the developing world, worms are a serious problem and millions of people suffer painful, debilitating diseases caused by parasitic nematodes such as Brugia malayi and Onchocerca volvulus. In the case of Onchocerca infection, young worms (microfilariae) spread throughout the body, often reaching the eye. While alive, these parasites appear to provoke a negligible immune response, but dead worms are an entirely different matter. Massive inflammation triggered by worm corpses results in tissue damage that, in the eye, often leads to blindness – hence the more common description of onchocerciasis as ‘river blindness’. The intriguing question is why dead worms should be so much worse than live worms. Now, Saint Andre and http://tcb.trends.com
colleagues have revealed the answer, and it isn’t the worms at all [1]. Onchocerca volvulus, like other nematodes and a wide variety of arthropods, plays host to intracellular bacteria of the genus Wolbachia. In insects, these bacteria appear to have evolved as parasites, but in nematodes they are essential endosymbionts – antibiotic treatment to eliminate Wolbachia renders the host nematode sterile. But, although these prokaryotic passengers might be crucial for the worm, they are bad news for the worm’s host. By treating Onchocerca with doxycycline, Saint Andre et al. were able to eliminate intracellular Wolbachia and thus produce worm extracts both with and without Wolbachia. They then injected these extracts into the corneas of mice and measured subsequent damage. The surprising result is that worm extracts lacking Wolbachia induce a much milder
inflammatory response than extracts from worms containing the bacteria. This Wolbachia-induced response is mediated, at least in part, by the Toll-like receptor 4 (TLR4) as mice with a mutated TLR4 react much less vigorously to Wolbachia-containing worms than do wild-type mice. Moreover, the authors go on to suggest that the blame lies not with the bacterium itself but with an endotoxin-like molecule that is produced by Wolbachia and released when the host worm dies. The intriguing question for the future is how many other disease-causing organisms are actually biological ‘Russian dolls’, harbouring the real culprit within their cells? 1 Saint Andre, A. et al. (2002) The role of endosymbiotic Wolbachia bacteria in the pathogenesis of river blindness. Science 295, 1892–1895
Robin C. May [email protected]
0962-8924/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved.
News & Comment
TRENDS in Cell Biology Vol.12 No.6 June 2002
Journal Club
Netrin and the GTPases Guidance molecules such as the netrins, the semaphorins or ephrins are key regulators of development of the central nervous system. These signals are thought to modulate neurite extension by providing instructive cues that act as attractants or repellents in different cell types. Current research focuses on the identification of the intracellular pathway leading to the regulation of the actin cytoskeleton required for such adapted cell behaviors. The small GTPases of the Rho family (RhoA, Rac1 and Cdc42) are largely involved in the transduction cascade ensuring the formation of filopodia (Cdc42) and lamellipodia (Rac1) of elongating growth cones. Therefore, it was logical to investigate recruitment of small GTPases during axonal guidance in response to semaphorins or ephrins. In this way, the interactions between Netrin-1 (a bifunctional guidance signal), DCC (‘deleted in colorectal cancer’, the receptor for Netrin-1) and Rho family members
Rac1 and Cdc42 have recently been explored [1,2]. Sherakabi and Kennedy [1] analyzed the consequence of inactivation of GTPases in different cell lines and growth cones following netrin-1-dependent filopodia extension. In their model, induced expression of DCC triggered an increase in the number of filopodia and cell-surface area when cells were exposed to netrin-1. Coexpression of DCC with dominant-negative forms of Cdc42 and Rac1 blocked upregulation of filopodia and augmentation of cell-surface area, respectively. Activation of these GTPases by netrin-1 was verified by detecting the amount of GTP-bound Cdc42 and Rac1 by western blot analysis. Interestingly, the authors showed that DCC was able to activate Cdc42 or Rac1 independently. A second study conducted by the group of Lamarche-Vane confirms the role of Cdc42 and Rac1 during neurite
extension and provides evidence for the requirement for downregulation of RhoA and Rho-kinase [2]. Future studies will have to elucidate the molecular nature of the protein(s) coupling DCC to GTPases. Because DCC is considered to be a tumor-suppressor gene, alongside the fundamental interest generated by elucidating the signaling pathway stemming from its activation, these studies could well shed light on the mechanisms controlling tumor progression. 1 Sherakabi, M. and Kennedy, T.E. (2002) The Netrin-1 receptor DCC promotes filopodia formation and cell spreading by activating Cdc42 and Rac1. Mol. Cell. Neurosci. 19, 1–17 2 Li, X. et al. Rac1 and Cdc42 but not RhoA or Rhokinase activities are required for neurite outgrowth induced by the Netrin-1 DCC (deleted in colorectal cancer) in N1E-115 neuroblastoma cells. J. Biol. Chem. (in press)
Dominique Bagnard [email protected]
Of Russian dolls and river blindness For those fortunate enough to live in the developed world, encounters with parasitic worms are usually more embarrassing than life-threatening, but, in the developing world, worms are a serious problem and millions of people suffer painful, debilitating diseases caused by parasitic nematodes such as Brugia malayi and Onchocerca volvulus. In the case of Onchocerca infection, young worms (microfilariae) spread throughout the body, often reaching the eye. While alive, these parasites appear to provoke a negligible immune response, but dead worms are an entirely different matter. Massive inflammation triggered by worm corpses results in tissue damage that, in the eye, often leads to blindness – hence the more common description of onchocerciasis as ‘river blindness’. The intriguing question is why dead worms should be so much worse than live worms. Now, Saint Andre and http://tcb.trends.com
colleagues have revealed the answer, and it isn’t the worms at all [1]. Onchocerca volvulus, like other nematodes and a wide variety of arthropods, plays host to intracellular bacteria of the genus Wolbachia. In insects, these bacteria appear to have evolved as parasites, but in nematodes they are essential endosymbionts – antibiotic treatment to eliminate Wolbachia renders the host nematode sterile. But, although these prokaryotic passengers might be crucial for the worm, they are bad news for the worm’s host. By treating Onchocerca with doxycycline, Saint Andre et al. were able to eliminate intracellular Wolbachia and thus produce worm extracts both with and without Wolbachia. They then injected these extracts into the corneas of mice and measured subsequent damage. The surprising result is that worm extracts lacking Wolbachia induce a much milder
inflammatory response than extracts from worms containing the bacteria. This Wolbachia-induced response is mediated, at least in part, by the Toll-like receptor 4 (TLR4) as mice with a mutated TLR4 react much less vigorously to Wolbachia-containing worms than do wild-type mice. Moreover, the authors go on to suggest that the blame lies not with the bacterium itself but with an endotoxin-like molecule that is produced by Wolbachia and released when the host worm dies. The intriguing question for the future is how many other disease-causing organisms are actually biological ‘Russian dolls’, harbouring the real culprit within their cells? 1 Saint Andre, A. et al. (2002) The role of endosymbiotic Wolbachia bacteria in the pathogenesis of river blindness. Science 295, 1892–1895
Robin C. May [email protected]
0962-8924/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved.