- Email: [email protected]
Roles of semaphorins and their receptors in laminar projection of hippocampal mossy fibers
486
Symposia & Short Talk Abstracts / Int. J. Devl Neuroscience 24 (2006) 471–493
environmental stimuli. In axon pathfinding in particular, both spatial and temporal patterns of Ca2+ signaling are essential for the responses of a neuronal growth cone to many guidance factors. I will discuss our recent findings on Ca2+ signaling during growth cone pathfinding and axon regeneration.
Control of myelination [S33] Axonal neuregulin-1 and intracellular PtdIns(3,4,5)P3 trigger myelin outgrowth by Schwann cells K. Armin-Nave 1,*, S. Goebbels 1, J. Oltrogge 1, C. Birchmeier 2, C. Lai 3, T. Fischer 1, M. Schwab 1
doi:10.1016/j.ijdevneu.2006.09.038
1
Max Planck Institute of Experimental Medicine, Germany; Max-Delbru¨ck-Centre, Germany; 3 Scripps Research Institute, USA
2
[S32] Roles of semaphorins and their receptors in laminar projection of hippocampal mossy fibers H. Fujisawa Mitchell 5
1,*
2
3
4
, F. Suto , T. Yagi , A. Che´dotal , K.J.
Nagoya University, Japan; 2 National Institute of Genetics, Japan; 3 Osaka University, Japan; 4 University of Paris, France; 5 Trinity College Dublin, Ireland E-mail address: [email protected] (H. Fujisawa).
1
The hippocampus is one of the good experimental models to elucidate cellular and molecular mechanisms that govern lamina-restricted termination of axons, because pyramidal cells, principal neurons of the cornu ammonis (CA), receive inputs from a variety of source in a lamina-specific fashion. For example, fibers from the dentate gyrus (mossy fibers) project preferentially to the proximal-most lamina of the suprapyramidal region of CA3. Molecular mechanisms that govern the laminal projection of the hippocampal afferents, however, have been unknown. We generated protein-null mutant mice for two semaphorin receptors, plexin-A2 and plexin-A4, and examined projection patterns of mossy fibers in the mutant animals. We here show that the deficiency of plexin-A2 causes the shift of mossy fibers from the suprapyramidal region to the infra- and intra-pyramidal regions, while the deficiency of plexin-A4 induces wide-spreading of mossy fibers within CA3. Immunohistochemical analyses reveal that the plexin-A4 proteins are distributed in mossy fibers. On the other hand, the plexin-A2 proteins are distributed in the suprapyramidal region of CA3 in a proximal-distal gradient. In vitro studies show that plexin-A4-deficient mossy fibers are unresponsive to the repulsive activities of Sema6A expressing in CA3. In addition, we show that the plexin-A2 loss-of-function phenotype is genetically suppressed by Sema6A loss-offunction. Based on these results, we propose a model for the lamina-restricted projection of mossy fibers; The expression of plexin-A4 on mossy fibers prevents them from entering the Sema6A-expressing suprapyramidal region of CA3 and restrict them to the proximal-most part where Sema6A repulsive activity is attenuated by plexin-A2. doi:10.1016/j.ijdevneu.2006.09.039
Myelination of axons is a prerequisite for rapid impulse conduction in the nervous system and essential for normal motor and cognitive functions. In the peripheral nervous system, Schwann cells (SC) either engulf multiple smallcaliber axons (Remak bundle), or single-out and spirally enwrap larger axons with a multi-lamellar myelin sheath. We have previously shown that axonal neuregulin-1 signaling to glial cells that express ErbB receptors is a critical regulator of myelination and myelin sheath thickness in vivo. Mice with reduced NRG1 gene dosage are hypomyelinated, whereas transgenic mice with elevated NRG1 expression in DRG and motoneurons are hypermyelinated. In the PNS, NRG1 type III is the responsible isoform. Whether NRG1 serves a similar function in the myelination of axons in the central nervous system is not known but of obvious clinical relevance. Also the molecular mechanisms downstream of ErbB receptor activation that initiate the spiral wrapping by SC are unknown. By targeting a null mutation of the PTEN gene to SC, we can demonstrate that the signaling lipid PtdIns(3,4,5)P3 (PIP3) induces myelin membrane outgrowth. In adult mice, elevated PIP3 activates Akt1 and causes hypermyelination as well as myelin outfoldings that resemble the pathology of human CMT4B. Surprisingly, elevated PIP3 is sufficient to induce the wrapping of small Cfiber axons in Remak bundels, and even the ensheathment of collagen fibers that completely lack axonal surface signals. These observations demonstrate a key role for PIP3 in inducing spiral wrapping and driving myelin membrane outgrowth. doi:10.1016/j.ijdevneu.2006.09.040 [S34] The role of extracellular matrix in the regulation of oligodendrocyte development and myelination J. Camara, J. Wang, C. ffrench-Constant * University of Cambridge, Department of Pathology and Centre for Brain Repair, UK Cell culture experiments examining growth factor signalling in oligodendrocytes show significant amplification by
Symposia & Short Talk Abstracts / Int. J. Devl Neuroscience 24 (2006) 471–493
environmental stimuli. In axon pathfinding in particular, both spatial and temporal patterns of Ca2+ signaling are essential for the responses of a neuronal growth cone to many guidance factors. I will discuss our recent findings on Ca2+ signaling during growth cone pathfinding and axon regeneration.
Control of myelination [S33] Axonal neuregulin-1 and intracellular PtdIns(3,4,5)P3 trigger myelin outgrowth by Schwann cells K. Armin-Nave 1,*, S. Goebbels 1, J. Oltrogge 1, C. Birchmeier 2, C. Lai 3, T. Fischer 1, M. Schwab 1
doi:10.1016/j.ijdevneu.2006.09.038
1
Max Planck Institute of Experimental Medicine, Germany; Max-Delbru¨ck-Centre, Germany; 3 Scripps Research Institute, USA
2
[S32] Roles of semaphorins and their receptors in laminar projection of hippocampal mossy fibers H. Fujisawa Mitchell 5
1,*
2
3
4
, F. Suto , T. Yagi , A. Che´dotal , K.J.
Nagoya University, Japan; 2 National Institute of Genetics, Japan; 3 Osaka University, Japan; 4 University of Paris, France; 5 Trinity College Dublin, Ireland E-mail address: [email protected] (H. Fujisawa).
1
The hippocampus is one of the good experimental models to elucidate cellular and molecular mechanisms that govern lamina-restricted termination of axons, because pyramidal cells, principal neurons of the cornu ammonis (CA), receive inputs from a variety of source in a lamina-specific fashion. For example, fibers from the dentate gyrus (mossy fibers) project preferentially to the proximal-most lamina of the suprapyramidal region of CA3. Molecular mechanisms that govern the laminal projection of the hippocampal afferents, however, have been unknown. We generated protein-null mutant mice for two semaphorin receptors, plexin-A2 and plexin-A4, and examined projection patterns of mossy fibers in the mutant animals. We here show that the deficiency of plexin-A2 causes the shift of mossy fibers from the suprapyramidal region to the infra- and intra-pyramidal regions, while the deficiency of plexin-A4 induces wide-spreading of mossy fibers within CA3. Immunohistochemical analyses reveal that the plexin-A4 proteins are distributed in mossy fibers. On the other hand, the plexin-A2 proteins are distributed in the suprapyramidal region of CA3 in a proximal-distal gradient. In vitro studies show that plexin-A4-deficient mossy fibers are unresponsive to the repulsive activities of Sema6A expressing in CA3. In addition, we show that the plexin-A2 loss-of-function phenotype is genetically suppressed by Sema6A loss-offunction. Based on these results, we propose a model for the lamina-restricted projection of mossy fibers; The expression of plexin-A4 on mossy fibers prevents them from entering the Sema6A-expressing suprapyramidal region of CA3 and restrict them to the proximal-most part where Sema6A repulsive activity is attenuated by plexin-A2. doi:10.1016/j.ijdevneu.2006.09.039
Myelination of axons is a prerequisite for rapid impulse conduction in the nervous system and essential for normal motor and cognitive functions. In the peripheral nervous system, Schwann cells (SC) either engulf multiple smallcaliber axons (Remak bundle), or single-out and spirally enwrap larger axons with a multi-lamellar myelin sheath. We have previously shown that axonal neuregulin-1 signaling to glial cells that express ErbB receptors is a critical regulator of myelination and myelin sheath thickness in vivo. Mice with reduced NRG1 gene dosage are hypomyelinated, whereas transgenic mice with elevated NRG1 expression in DRG and motoneurons are hypermyelinated. In the PNS, NRG1 type III is the responsible isoform. Whether NRG1 serves a similar function in the myelination of axons in the central nervous system is not known but of obvious clinical relevance. Also the molecular mechanisms downstream of ErbB receptor activation that initiate the spiral wrapping by SC are unknown. By targeting a null mutation of the PTEN gene to SC, we can demonstrate that the signaling lipid PtdIns(3,4,5)P3 (PIP3) induces myelin membrane outgrowth. In adult mice, elevated PIP3 activates Akt1 and causes hypermyelination as well as myelin outfoldings that resemble the pathology of human CMT4B. Surprisingly, elevated PIP3 is sufficient to induce the wrapping of small Cfiber axons in Remak bundels, and even the ensheathment of collagen fibers that completely lack axonal surface signals. These observations demonstrate a key role for PIP3 in inducing spiral wrapping and driving myelin membrane outgrowth. doi:10.1016/j.ijdevneu.2006.09.040 [S34] The role of extracellular matrix in the regulation of oligodendrocyte development and myelination J. Camara, J. Wang, C. ffrench-Constant * University of Cambridge, Department of Pathology and Centre for Brain Repair, UK Cell culture experiments examining growth factor signalling in oligodendrocytes show significant amplification by