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Integrin and the Reelin-Dab1 pathway: a sticky affair?
Developmental Brain Research 152 (2004) 269 – 271 www.elsevier.com/locate/devbrainres
Short communication
Integrin and the Reelin-Dab1 pathway: a sticky affair? Juan M. Luque * Instituto de Neurociencias, Universidad Miguel Herna´ndez-Consejo Superior de Investigaciones Cientı´ficas, Campus de San Juan s/n, E-03550 San Juan de Alicante, Alicante, Spain Accepted 17 June 2004 Available online 28 July 2004
Abstract It has been repeatedly suggested that integrin is essential for neuronal migration. A new study proposes a link between Disabled-1 (Dab1) phosphorylation and alpha3 integrin signalling that is thought to drive the timely detachment of migrating neurons from the guiding radial glia fibers during early corticogenesis. This proposal however is hardly compatible with time-lapse anatomical investigations and genetic studies on integrin or with recent works which indicate direct reelin signalling to radial fibers. D 2004 Elsevier B.V. All rights reserved. Keywords: Reelin signalling pathway; Integrin; Radial glia; Radial fiber; Neuronal migration; Neuronal positioning; Cortical layering
1. Comment on ‘‘Disabled-1-Regulated Adhesion of Migrating Neurons to Radial Glial Fiber Contributes to Neuronal Positioning during Early Corticogenesis’’ The very nature of nearly all neurodevelopmental processes, including neuronal migration, requires the involvement of a variety of molecules ranging from transcription factors, extracellular matrix proteins, receptors, adhesion molecules, diffusible and intracellular signalling molecules, and components of associated signalling cascades. Genetic and biochemical studies have revealed that the ReelinDisabled-1 (Dab1) signalling pathway is critically involved in the positioning of migrating neurons during CNS development. Mice deficient in the secreted extracellular matrix glycoprotein reelin, ApoER2 and VLDLR reelin receptors or the intracellular adapter protein Dab1, show analogous neuronal positioning defects, with inversion of neuronal layers in the cerebral cortex and laminar defects in the hippocampus and cerebellum [13]. However, little is known and much interest exists as to how the signalling events are linked to the behaviour of individual neurons during migration [6]. Recently, Sanada et al. [14] reported in Neuron that the abnormal migration of neurons in the cortex of Dab1-
* Tel.: +34-965-919205; fax: +34-965-919561. E-mail address: [email protected] (J.M. Luque). 0165-3806/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.devbrainres.2004.06.005
deficient mice is associated with an impaired detachment from radial fibers of clonally related radial glial cells. Their work claims a link between Dab1 phosphorylation and alpha3 integrin signalling that drives the timely detachment of migrating neurons from the guiding radial glia fibers, thereby regulating proper neuronal positioning during corticogenesis. Their evidence was for the most part histological: First, GFP-retrovirus infection was used to label radial glial cells and their neuronal progeny at an early stage of cortical development. The spatial relationship was then analyzed between migrating neuronal-like profiles and a clonally related fiber belonging to a radial glial cell-like profile. Because such neuronal profiles were ‘‘seemingly in contact with the fiber of its mother radial glia’’, it was assumed that migrating neurons moved alongside their parental radial glial fibers, and therefore the shortest distance between the centroid position of an early GFP-labelled neuronal profile and a clonally related radial fiber was used to represent the amount of adhesion between both cellular entities. Certainly, conclusive observations regarding neuronal behaviour during migration have proven difficult to obtain and interpret since Cajal’s times. There is now mounting evidence that during early cortical development, basal fibers of radial glial inherited by daughter neurons are used directly for their somal translocation from the germinal zone to the cortical plate [9,11,15]. Sanada et al. [14] take little notice of this in their desire to quantify and compare the amount of adhesion of migrating neurons to radial glial
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J.M. Luque / Developmental Brain Research 152 (2004) 269–271
fibers in wild-type and Dab1-deficient cortices. Whatever the possible meaning of the reported differences, it is highly unlikely to be related to a regulated adhesion of migrating neurons to radial glial fibers, particularly when the radial fiber could be part of the neuronal entity. Evidence suggesting direct Reelin-Dab1 signalling to radial glial fibers [4,6] seems also at odds with such a proposal. Sanada et al. [14] also reported differences in the mode and tempo of cellular migration with slower average speed of migration in Dab1 mutant as compared to wild-type cortices. In fact, the difficulty when interpreting most of the results of this work becomes even more obvious when one takes into consideration two recent time-lapse investigations with clonally related cellular profiles in slice culture of early [10] and late [12] embryonic cortex. Miyata et al. [10] have further documented the intricate choreography of radial process inheritance from ventricular and subventricular (intermediate) dividing cortical progenitors. During early corticogenesis, most divisions at the ventricular surface generated paired cycling daughters (P/P division). They found that 23% of P/P divisions gave rise to two daughter cells that divided at the ventricular surface. One daughter cell inherited the parent basal process whereas the other extended a new process to the pial surface. The trajectory of the interkinetic nuclear movement often differed between such paired surface-dividing cells, with quicker and greater ascent by the inheritors of the basal process. Within a single cell cycle, 77% of P/P divisions at the ventricular zone supplied one mitotic daughter cell to a nonsurface position at the subventricular zone whilst retaining the other mitotic daughter cell at the ventricular surface. The frequency of inheritance of the parental basal process is roughly equal between nonsurface and surface daughters. The nonsuperficial daughter often generates a couple o neurons, some of which will inherit the parental basal process. Some—though not all—of these cells are quickly inserted into the cortical plate [10]. Clearly, the interpretation of histological results by Sanada et al. [14] takes into account neither somal translocation as an important mode of migration nor the relationship between basal process inheritance and the speed of cellular migration. On the other hand, Noctor et al. [12] analyzed the modes of neuronal migration in great detail by measuring four different phases of migration for individual cells and how the speed of migration differed for the distinct phases. The migration speed reported by Sanada et al. [14] for wild-type cells is way above the migration speed measured by Noctor et al. in phase 4 of migration (the long-range migration towards the pia). In contrast, Dab1 mutant cells move at approximately the speed of wild-type cells in the Noctor study. Certainly, it would be worth knowing the actual migratory phase/mode analyzed by Sanada et al. [14] in their earlier wild-type and mutant cortices. This also could well influence the interpretation of the results. Likewise, regardless of how Reelin-Dab1 and integrin signalling pathways could be interacting (at present un-
known), a model in which reelin modulates cell adhesion properties through interactions with alpha3beta1 integrin [2] is not supported by genetic studies on beta1 integrin [3,7]. Further at odds, the proposal that the integrin alpha3beta1 is required to mediate a reelin ‘‘stop signal’’ onto migrating neurons [2] is not supported by the results of the in vivo expression of ectopic reelin [8]. In my view, although it is not impossible that both signalling pathways work together [1,5], the regulated adhesion of migrating neurons to radial glial fibers during early corticogenesis does not appear to be particularly relevant in such a context. Thus, bearing in mind all this scenario, I remain doubtful about the actual meaning of the spatial relationship between the clonally related fibers and profiles proposed by Sanada et al. [14], and as to whether the reported spatial and migration speed differences between wild-type and Dab1 mutant cells have anything to do with regulated adhesion.
Acknowledgements Thanks are due to Stuart B. Ingham for help with English editing. JML is a ‘‘Ramo´n y Cajal’’ Research Fellow.
References [1] B.A. Ballif, L. Arnaud, W.T. Arthur, D. Guris, A. Imamoto, J.A. Cooper, Activation of a Dab1/CrkL/C3G/Rap1 pathway in reelin stimulated neurons, Curr. Biol. 14 (2004) 606 – 610. [2] L. Dulabon, E.C. Olson, M.G. Taglienti, S. Eisenhuth, B. McGrath, C.A. Walsh, J.A. Kreidberg, E.S. Anton, Reelin binds alpha3beta1 integrin and inhibits neuronal migration, Neuron 27 (2000) 33 – 44. [3] D. Graus-Porta, S. Blaess, M. Senften, A. Littlewood-Evans, C. Damsky, Z. Huang, P. Orban, R. Klein, J.C. Schittny, U. Muller, Beta1-class integrins regulate the development of lamina and folia in the cerebral and cerebellar cortex, Neuron 31 (2001) 367 – 379. [4] E. Hartfuss, E. Foster, H.H. Bock, M.A. Hack, P. Leprince, J.M. Luque, J. Herz, M. Frotscher, M. Gotz, Reelin signaling directly affects radial glia morphology and biochemical maturation, Development 130 (2003) 4597 – 4609. [5] Y. Huang, S. Magdaleno, R. Hopkins, C. Slaughter, T. Curran, L. Keshvara, Tyrosine phosphorylated disabled 1 recruits Crk family adapater proteins, Biochem. Biophys. Res. Commun. 318 (2004) 204 – 212. [6] J.M. Luque, J. Morante-Oria, A. Fairen, Localization of ApoER2, VLDLR and Dab1 in radial glia: groundwork for a new model of reelin action during cortical development, Dev. Brain Res. 140 (2003) 195 – 203. [7] S.M. Magdaleno, T. Curran, Brain development: integrin and the reelin pathway, Curr. Biol. 11 (2001) R1032 – R1035. [8] S. Magdaleno, L. Keshvara, T. Curran, Rescue of ataxia and preplate splitting by ectopic expresio´n of reelin in reeler mice, Neuron 33 (2002) 573 – 586. [9] T. Miyata, A. Kawaguchi, H. Okano, M. Ogawa, Asymmetric inheritance of radial glial fibers by cortical neurons, Neuron 31 (2001) 727 – 741. [10] T. Miyata, A. Kawaguchi, K. Saito, M. Kawano, T. Muto, M. Ogawa, Asymmetric production of surface-dividing and non-surface-dividing cortical progenitor cells, Development 131 (2004) 3133 – 3145.
J.M. Luque / Developmental Brain Research 152 (2004) 269–271 [11] D.K. Morest, J. Silver, Precursors of neurons, neuroglia, and ependymal cells in the CNS: what are they? Where are they from? How do they get where they are going? Glia 43 (2003) 6 – 18. [12] S.C. Noctor, V. Martı´nez-Cerden˜o, L. Ivic, A.R. Kriegstein, Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases, Nat. Neurosci. 7 (2004) 136 – 144. [13] D.S. Rice, T. Curran, Role of the reelin signaling pathway in central nervous system development, Annu. Rev. Neurosci. 24 (2001) 1005 – 1039.
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[14] K. Sanada, A. Gupta, L.-H. Tsai, Disabled-1-regulated adhesion of migrating neurons to radial glial fiber contributes to neuronal positioning during early corticogenesis, Neuron 42 (2004) 197 – 211. [15] N. Tamamaki, K. Nakamura, K. Okamoto, T. Kaneko, Radial glia is a progenitor of neocortical neurons in the developing cerebral cortex, Neurosci. Res. 41 (2001) 51 – 60.
Short communication
Integrin and the Reelin-Dab1 pathway: a sticky affair? Juan M. Luque * Instituto de Neurociencias, Universidad Miguel Herna´ndez-Consejo Superior de Investigaciones Cientı´ficas, Campus de San Juan s/n, E-03550 San Juan de Alicante, Alicante, Spain Accepted 17 June 2004 Available online 28 July 2004
Abstract It has been repeatedly suggested that integrin is essential for neuronal migration. A new study proposes a link between Disabled-1 (Dab1) phosphorylation and alpha3 integrin signalling that is thought to drive the timely detachment of migrating neurons from the guiding radial glia fibers during early corticogenesis. This proposal however is hardly compatible with time-lapse anatomical investigations and genetic studies on integrin or with recent works which indicate direct reelin signalling to radial fibers. D 2004 Elsevier B.V. All rights reserved. Keywords: Reelin signalling pathway; Integrin; Radial glia; Radial fiber; Neuronal migration; Neuronal positioning; Cortical layering
1. Comment on ‘‘Disabled-1-Regulated Adhesion of Migrating Neurons to Radial Glial Fiber Contributes to Neuronal Positioning during Early Corticogenesis’’ The very nature of nearly all neurodevelopmental processes, including neuronal migration, requires the involvement of a variety of molecules ranging from transcription factors, extracellular matrix proteins, receptors, adhesion molecules, diffusible and intracellular signalling molecules, and components of associated signalling cascades. Genetic and biochemical studies have revealed that the ReelinDisabled-1 (Dab1) signalling pathway is critically involved in the positioning of migrating neurons during CNS development. Mice deficient in the secreted extracellular matrix glycoprotein reelin, ApoER2 and VLDLR reelin receptors or the intracellular adapter protein Dab1, show analogous neuronal positioning defects, with inversion of neuronal layers in the cerebral cortex and laminar defects in the hippocampus and cerebellum [13]. However, little is known and much interest exists as to how the signalling events are linked to the behaviour of individual neurons during migration [6]. Recently, Sanada et al. [14] reported in Neuron that the abnormal migration of neurons in the cortex of Dab1-
* Tel.: +34-965-919205; fax: +34-965-919561. E-mail address: [email protected] (J.M. Luque). 0165-3806/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.devbrainres.2004.06.005
deficient mice is associated with an impaired detachment from radial fibers of clonally related radial glial cells. Their work claims a link between Dab1 phosphorylation and alpha3 integrin signalling that drives the timely detachment of migrating neurons from the guiding radial glia fibers, thereby regulating proper neuronal positioning during corticogenesis. Their evidence was for the most part histological: First, GFP-retrovirus infection was used to label radial glial cells and their neuronal progeny at an early stage of cortical development. The spatial relationship was then analyzed between migrating neuronal-like profiles and a clonally related fiber belonging to a radial glial cell-like profile. Because such neuronal profiles were ‘‘seemingly in contact with the fiber of its mother radial glia’’, it was assumed that migrating neurons moved alongside their parental radial glial fibers, and therefore the shortest distance between the centroid position of an early GFP-labelled neuronal profile and a clonally related radial fiber was used to represent the amount of adhesion between both cellular entities. Certainly, conclusive observations regarding neuronal behaviour during migration have proven difficult to obtain and interpret since Cajal’s times. There is now mounting evidence that during early cortical development, basal fibers of radial glial inherited by daughter neurons are used directly for their somal translocation from the germinal zone to the cortical plate [9,11,15]. Sanada et al. [14] take little notice of this in their desire to quantify and compare the amount of adhesion of migrating neurons to radial glial
270
J.M. Luque / Developmental Brain Research 152 (2004) 269–271
fibers in wild-type and Dab1-deficient cortices. Whatever the possible meaning of the reported differences, it is highly unlikely to be related to a regulated adhesion of migrating neurons to radial glial fibers, particularly when the radial fiber could be part of the neuronal entity. Evidence suggesting direct Reelin-Dab1 signalling to radial glial fibers [4,6] seems also at odds with such a proposal. Sanada et al. [14] also reported differences in the mode and tempo of cellular migration with slower average speed of migration in Dab1 mutant as compared to wild-type cortices. In fact, the difficulty when interpreting most of the results of this work becomes even more obvious when one takes into consideration two recent time-lapse investigations with clonally related cellular profiles in slice culture of early [10] and late [12] embryonic cortex. Miyata et al. [10] have further documented the intricate choreography of radial process inheritance from ventricular and subventricular (intermediate) dividing cortical progenitors. During early corticogenesis, most divisions at the ventricular surface generated paired cycling daughters (P/P division). They found that 23% of P/P divisions gave rise to two daughter cells that divided at the ventricular surface. One daughter cell inherited the parent basal process whereas the other extended a new process to the pial surface. The trajectory of the interkinetic nuclear movement often differed between such paired surface-dividing cells, with quicker and greater ascent by the inheritors of the basal process. Within a single cell cycle, 77% of P/P divisions at the ventricular zone supplied one mitotic daughter cell to a nonsurface position at the subventricular zone whilst retaining the other mitotic daughter cell at the ventricular surface. The frequency of inheritance of the parental basal process is roughly equal between nonsurface and surface daughters. The nonsuperficial daughter often generates a couple o neurons, some of which will inherit the parental basal process. Some—though not all—of these cells are quickly inserted into the cortical plate [10]. Clearly, the interpretation of histological results by Sanada et al. [14] takes into account neither somal translocation as an important mode of migration nor the relationship between basal process inheritance and the speed of cellular migration. On the other hand, Noctor et al. [12] analyzed the modes of neuronal migration in great detail by measuring four different phases of migration for individual cells and how the speed of migration differed for the distinct phases. The migration speed reported by Sanada et al. [14] for wild-type cells is way above the migration speed measured by Noctor et al. in phase 4 of migration (the long-range migration towards the pia). In contrast, Dab1 mutant cells move at approximately the speed of wild-type cells in the Noctor study. Certainly, it would be worth knowing the actual migratory phase/mode analyzed by Sanada et al. [14] in their earlier wild-type and mutant cortices. This also could well influence the interpretation of the results. Likewise, regardless of how Reelin-Dab1 and integrin signalling pathways could be interacting (at present un-
known), a model in which reelin modulates cell adhesion properties through interactions with alpha3beta1 integrin [2] is not supported by genetic studies on beta1 integrin [3,7]. Further at odds, the proposal that the integrin alpha3beta1 is required to mediate a reelin ‘‘stop signal’’ onto migrating neurons [2] is not supported by the results of the in vivo expression of ectopic reelin [8]. In my view, although it is not impossible that both signalling pathways work together [1,5], the regulated adhesion of migrating neurons to radial glial fibers during early corticogenesis does not appear to be particularly relevant in such a context. Thus, bearing in mind all this scenario, I remain doubtful about the actual meaning of the spatial relationship between the clonally related fibers and profiles proposed by Sanada et al. [14], and as to whether the reported spatial and migration speed differences between wild-type and Dab1 mutant cells have anything to do with regulated adhesion.
Acknowledgements Thanks are due to Stuart B. Ingham for help with English editing. JML is a ‘‘Ramo´n y Cajal’’ Research Fellow.
References [1] B.A. Ballif, L. Arnaud, W.T. Arthur, D. Guris, A. Imamoto, J.A. Cooper, Activation of a Dab1/CrkL/C3G/Rap1 pathway in reelin stimulated neurons, Curr. Biol. 14 (2004) 606 – 610. [2] L. Dulabon, E.C. Olson, M.G. Taglienti, S. Eisenhuth, B. McGrath, C.A. Walsh, J.A. Kreidberg, E.S. Anton, Reelin binds alpha3beta1 integrin and inhibits neuronal migration, Neuron 27 (2000) 33 – 44. [3] D. Graus-Porta, S. Blaess, M. Senften, A. Littlewood-Evans, C. Damsky, Z. Huang, P. Orban, R. Klein, J.C. Schittny, U. Muller, Beta1-class integrins regulate the development of lamina and folia in the cerebral and cerebellar cortex, Neuron 31 (2001) 367 – 379. [4] E. Hartfuss, E. Foster, H.H. Bock, M.A. Hack, P. Leprince, J.M. Luque, J. Herz, M. Frotscher, M. Gotz, Reelin signaling directly affects radial glia morphology and biochemical maturation, Development 130 (2003) 4597 – 4609. [5] Y. Huang, S. Magdaleno, R. Hopkins, C. Slaughter, T. Curran, L. Keshvara, Tyrosine phosphorylated disabled 1 recruits Crk family adapater proteins, Biochem. Biophys. Res. Commun. 318 (2004) 204 – 212. [6] J.M. Luque, J. Morante-Oria, A. Fairen, Localization of ApoER2, VLDLR and Dab1 in radial glia: groundwork for a new model of reelin action during cortical development, Dev. Brain Res. 140 (2003) 195 – 203. [7] S.M. Magdaleno, T. Curran, Brain development: integrin and the reelin pathway, Curr. Biol. 11 (2001) R1032 – R1035. [8] S. Magdaleno, L. Keshvara, T. Curran, Rescue of ataxia and preplate splitting by ectopic expresio´n of reelin in reeler mice, Neuron 33 (2002) 573 – 586. [9] T. Miyata, A. Kawaguchi, H. Okano, M. Ogawa, Asymmetric inheritance of radial glial fibers by cortical neurons, Neuron 31 (2001) 727 – 741. [10] T. Miyata, A. Kawaguchi, K. Saito, M. Kawano, T. Muto, M. Ogawa, Asymmetric production of surface-dividing and non-surface-dividing cortical progenitor cells, Development 131 (2004) 3133 – 3145.
J.M. Luque / Developmental Brain Research 152 (2004) 269–271 [11] D.K. Morest, J. Silver, Precursors of neurons, neuroglia, and ependymal cells in the CNS: what are they? Where are they from? How do they get where they are going? Glia 43 (2003) 6 – 18. [12] S.C. Noctor, V. Martı´nez-Cerden˜o, L. Ivic, A.R. Kriegstein, Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases, Nat. Neurosci. 7 (2004) 136 – 144. [13] D.S. Rice, T. Curran, Role of the reelin signaling pathway in central nervous system development, Annu. Rev. Neurosci. 24 (2001) 1005 – 1039.
271
[14] K. Sanada, A. Gupta, L.-H. Tsai, Disabled-1-regulated adhesion of migrating neurons to radial glial fiber contributes to neuronal positioning during early corticogenesis, Neuron 42 (2004) 197 – 211. [15] N. Tamamaki, K. Nakamura, K. Okamoto, T. Kaneko, Radial glia is a progenitor of neocortical neurons in the developing cerebral cortex, Neurosci. Res. 41 (2001) 51 – 60.