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Cell numbers: can they be controlled without programmed cell death?
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News & Comment
TRENDS in Neurosciences Vol.24 No.1 January 2001
Letters
Under pressure Although detection of osmotic stimuli is essential for all organisms, few osmoreceptors proteins – none of them in vertebrates – were known. Using a candidate gene approach, Liedtke et al. have now cloned cDNAs encoding the vanilloid receptor-related osmotically activated channel (VR-OAC) from the rat, mouse, human and chicken. In vitro studies showed that this novel protein acts as a poorly selective vertebrate cation channel that is gated by osmotic stress. Accordingly, neurosensory cells, which have been shown to respond to osmotic pressure, were shown to express VR-OAC. A fuller understanding of the role of this ion channel awaits the results of analysis of gene-targeted mice. Cell (2000) 103, 525–535.
Cell numbers: can they be controlled without programmed cell death? Mathias Bähr1 states that programmed cell death (PCD) ‘is necessary to control the final cell numbers of neurons and glia in the CNS and PNS’. Although it is obvious that the final number will be influenced by PCD, the implication that without PCD, cell numbers could not be controlled, has often been implicit in discussions of cell death. Does any reader know of evidence for any well defined neuronal population where before the period of cell death, or in the absence of cell death, inter individual variability in cell number is higher than it is in a normal population after PCD? This could provide strong evidence for the hypothesis that cell death is necessary as a method for ‘controlling’ cell numbers. R.W. Guillery Dept of Anatomy, University of Wisconsin, School of Medicine,1300, University Ave, Madison, WI 53706, USA.
BMP it up! A more complex, but clearer, picture is emerging for the role of certain bone morphogenetic proteins (BMPs) and their role in olfactory epithelium (OE) neurogenesis. Evidence presented in a paper by Anne Calof and colleagues demonstrates that in addition to inhibiting neurogenesis, certain BMPs, such as BMP4, may promote OE neurogenesis. Importantly, BMP4 does not affect proliferation of progenitor cells. How are these differential effects achieved? The type of BMP appears to be a factor, as does its concentration; other important determinants are cell type and lineage state. Another control point is provided by endogenous regulators of BMPs such as noggin, which itself is regulated by nogginbinding factors produced by OE stroma. By inhibiting proliferation of progenitor cells but stimulating neurogeneisis, these data may provide a potential explanation for the slowing rate of neurogenesis in the developing CNS. Development (2000) 127, 5403–5413.
Reference 1 Bähr, M. (2000) Live or let die – retinal ganglion cell death and survival during development and in the lesioned adult CNS. Trends Neurosci. 23, 483–490 PII: S0166-2236(00)01706-9
Serine proteases and brain damage – contribution of the urokinaseplasminogen activator system Gingrich and Traynelis1 gave a stimulating review of the potential pathological mechanisms triggered by serine proteases in CNS diseases. In addition to those mentioned, there are further serine protease systems with highly bioactive members that traffick into CNS lesions resulting in tissue degradation, debris formation and removal, neuronal damage and blood–brain barrier modulation, and are also considered of crucial importance to
angiogenesis, inflammation and tumor growth. Several recent data underscore the importance of the urokinase plasminogen activator (uPA) system consisting of the uPA receptor (uPAR), uPA and its inhibitor, plasminogen activator inhibitor (PAI-I) in nervous system pathophysiology. Such data include proteolysis, cell recruitment and adhesion, which rely on uPA interactions with uPAR (CD87) and PAI-I (Fig. 1a). Activation of this protein system induces drastic active reorganization of the cytoskeleton (phosphorylation of specific cytokeratins), has chemotactic activity (chemotactic epitope of cell-surface bound, cleaved uPAR), affects cell adhesion (direct interaction of uPAR with vitronectin and integrins) and cell migration (motogenic effect by chemotactic, cleaved uPAR). A further proangiogenetic role during revascularization has been suggested using homologous uPA knockout (uPA−/−)mice2. These effects might be induced either directly or indirectly by recruiting secondary effector mechanisms, such as the metalloproteinase system (MMP’s)3 or plasmin. Gingrich and Traynelis1 highlighted the need for identification of protease receptor functions exerting specific biological effects. Interestingly, in this regard, the uniqueness of the uPA–uPAR complex lies in its cell-surface receptor uPAR (Refs 4–6). In human brains we observed dramatic changes from a low level of intrinsic uPAR expression to extensive expression in response to stroke and brain trauma (Fig. 1b). Furthermore, uPAR upregulation was clearly caused by invading blood-derived cells because expression was apparent on inflammatory cells, such as granulocytes invading monocytes and lymphocytes, which were not found in the brain parenchyma under physiologic conditions. These cells were upregulated in perivascular Virchow–Robin spaces7, representing the major drainage route for extravasating cells into the brain. Because brain entry triggered by inflammation is not solely a mechanism used by the uPAR-uPA-PAI-I system, blood–brain barrier leakage is widespread and also permissive for thrombin or tPA. Therefore, because the post-injury inflammatory response acts as an entry and major delivery mechanism of serine proteases into the brain, it might
http://tins.trends.com 0166-2236/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII:
News & Comment
TRENDS in Neurosciences Vol.24 No.1 January 2001
Letters
Under pressure Although detection of osmotic stimuli is essential for all organisms, few osmoreceptors proteins – none of them in vertebrates – were known. Using a candidate gene approach, Liedtke et al. have now cloned cDNAs encoding the vanilloid receptor-related osmotically activated channel (VR-OAC) from the rat, mouse, human and chicken. In vitro studies showed that this novel protein acts as a poorly selective vertebrate cation channel that is gated by osmotic stress. Accordingly, neurosensory cells, which have been shown to respond to osmotic pressure, were shown to express VR-OAC. A fuller understanding of the role of this ion channel awaits the results of analysis of gene-targeted mice. Cell (2000) 103, 525–535.
Cell numbers: can they be controlled without programmed cell death? Mathias Bähr1 states that programmed cell death (PCD) ‘is necessary to control the final cell numbers of neurons and glia in the CNS and PNS’. Although it is obvious that the final number will be influenced by PCD, the implication that without PCD, cell numbers could not be controlled, has often been implicit in discussions of cell death. Does any reader know of evidence for any well defined neuronal population where before the period of cell death, or in the absence of cell death, inter individual variability in cell number is higher than it is in a normal population after PCD? This could provide strong evidence for the hypothesis that cell death is necessary as a method for ‘controlling’ cell numbers. R.W. Guillery Dept of Anatomy, University of Wisconsin, School of Medicine,1300, University Ave, Madison, WI 53706, USA.
BMP it up! A more complex, but clearer, picture is emerging for the role of certain bone morphogenetic proteins (BMPs) and their role in olfactory epithelium (OE) neurogenesis. Evidence presented in a paper by Anne Calof and colleagues demonstrates that in addition to inhibiting neurogenesis, certain BMPs, such as BMP4, may promote OE neurogenesis. Importantly, BMP4 does not affect proliferation of progenitor cells. How are these differential effects achieved? The type of BMP appears to be a factor, as does its concentration; other important determinants are cell type and lineage state. Another control point is provided by endogenous regulators of BMPs such as noggin, which itself is regulated by nogginbinding factors produced by OE stroma. By inhibiting proliferation of progenitor cells but stimulating neurogeneisis, these data may provide a potential explanation for the slowing rate of neurogenesis in the developing CNS. Development (2000) 127, 5403–5413.
Reference 1 Bähr, M. (2000) Live or let die – retinal ganglion cell death and survival during development and in the lesioned adult CNS. Trends Neurosci. 23, 483–490 PII: S0166-2236(00)01706-9
Serine proteases and brain damage – contribution of the urokinaseplasminogen activator system Gingrich and Traynelis1 gave a stimulating review of the potential pathological mechanisms triggered by serine proteases in CNS diseases. In addition to those mentioned, there are further serine protease systems with highly bioactive members that traffick into CNS lesions resulting in tissue degradation, debris formation and removal, neuronal damage and blood–brain barrier modulation, and are also considered of crucial importance to
angiogenesis, inflammation and tumor growth. Several recent data underscore the importance of the urokinase plasminogen activator (uPA) system consisting of the uPA receptor (uPAR), uPA and its inhibitor, plasminogen activator inhibitor (PAI-I) in nervous system pathophysiology. Such data include proteolysis, cell recruitment and adhesion, which rely on uPA interactions with uPAR (CD87) and PAI-I (Fig. 1a). Activation of this protein system induces drastic active reorganization of the cytoskeleton (phosphorylation of specific cytokeratins), has chemotactic activity (chemotactic epitope of cell-surface bound, cleaved uPAR), affects cell adhesion (direct interaction of uPAR with vitronectin and integrins) and cell migration (motogenic effect by chemotactic, cleaved uPAR). A further proangiogenetic role during revascularization has been suggested using homologous uPA knockout (uPA−/−)mice2. These effects might be induced either directly or indirectly by recruiting secondary effector mechanisms, such as the metalloproteinase system (MMP’s)3 or plasmin. Gingrich and Traynelis1 highlighted the need for identification of protease receptor functions exerting specific biological effects. Interestingly, in this regard, the uniqueness of the uPA–uPAR complex lies in its cell-surface receptor uPAR (Refs 4–6). In human brains we observed dramatic changes from a low level of intrinsic uPAR expression to extensive expression in response to stroke and brain trauma (Fig. 1b). Furthermore, uPAR upregulation was clearly caused by invading blood-derived cells because expression was apparent on inflammatory cells, such as granulocytes invading monocytes and lymphocytes, which were not found in the brain parenchyma under physiologic conditions. These cells were upregulated in perivascular Virchow–Robin spaces7, representing the major drainage route for extravasating cells into the brain. Because brain entry triggered by inflammation is not solely a mechanism used by the uPAR-uPA-PAI-I system, blood–brain barrier leakage is widespread and also permissive for thrombin or tPA. Therefore, because the post-injury inflammatory response acts as an entry and major delivery mechanism of serine proteases into the brain, it might
http://tins.trends.com 0166-2236/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: