Expression of constitutively active p21H‐rasval12 in postmitotic pyramidal neurons results in increased dendritic size and complexity

The small G protein p21Ras is a critical molecular switch for relaying neurotrophic actions and is essential for normal functioning and plasticity of the nervous system. In this study, the morphogenetic effects of p21Ras were investigated on neurons in vivo. Morphological changes of layers II/III and Vb commissural pyramidal neurons of the primary somatosensory cortex were analyzed in transgenic mice expressing permanently active p21H‐RasVal12 in postmitotic neurons. Pyramidal cells were retrogradely labelled with biotinylated dextran amine and subsequently traced using Neurolucida. Compared with wild‐type mice, transgenic animals showed a significant increase in the surface area and volume of basal dendrites on the proximal and intermediate segments in layers II/III and on further distal segments in layer V. In addition, the surface area and volume of the trunk and of the proximal segments of oblique branches of apical dendrites were enlarged in both layers. Sholl analyses of basal and apical dendrites showed a significant increase in dendritic complexity of layer V neurons. A positive correlation was observed between the size of the basal dendrite and the neuronal soma size in the transgenic population, indicating that growth‐promoting effects of p21H‐RasVal12 affect both cellular compartments in parallel. However, the dendritic surface correlated with the number of tips and dendritic stem diameter in both wild‐type and transgenic populations, demonstrating that these relations represent rather conservative design principles in dendritic morphology. The data presented here suggest an important role of p21Ras‐dependent signaling in the final differentiation and maintenance of dendritic morphology. J. Comp. Neurol. 467:119–133, 2003. © 2003 Wiley‐Liss, Inc.

[1]  Ramón y Cajal,et al.  Histologie du système nerveux de l'homme & des vertébrés , 1909 .

[2]  J. Eayrs,et al.  Postnatal development of the cerebral cortex in the rat. , 1959, Journal of anatomy.

[3]  M. Colonnier.  Synaptic patterns on different cell types in the different laminae of the cat visual cortex. An electron microscope study. , 1968, Brain research.

[4]  D. Bray.  BRANCHING PATTERNS OF INDIVIDUAL SYMPATHETIC NEURONS IN CULTURE , 1973, The Journal of cell biology.

[5]  P. Rakić,et al.  Role of cell interaction in development of dendritic patterns. , 1975, Advances in neurology.

[6]  Braitenberg,et al.  Cortical architectonics: General and areal , 1978 .

[7]  S. Wise,et al.  Maturation of pyramidal cell form in relation to developing afferent and efferent connections of rat somatic sensory cortex , 1979, Neuroscience.

[8]  E. Fifková,et al.  A Golgi study of the early postnatal development of the visual cortex of the hooded rat , 1979, The Journal of comparative neurology.

[9]  W M Cowan,et al.  Further observations on hippocampal neurons in dispersed cell culture , 1979, The Journal of comparative neurology.

[10]  Michael Miller.  Maturation of rat visual cortex. I. A quantitative study of Golgi-impregnated pyramidal neurons , 1981, Journal of neurocytology.

[11]  J. Juraska.  The development of pyramidal neurons after eye opening in the visual cortex of hooded rats: A quantitative study , 1982, The Journal of comparative neurology.

[12]  G. Banker,et al.  An electron microscopic study of the development of axons and dendrites by hippocampal neurons in culture. I. Cells which develop without intercellular contacts , 1984, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[13]  R. Verwer,et al.  Synaptic characteristics of identified pyramidal and multipolar non-pyramidal neurons in the visual cortex of young and adult rabbits. A quantitative Golgi-electron microscope study , 1984, Neuroscience.

[14]  R. R. Sturrock,et al.  Cerebral Cortex, vol 1. Cellular Components of the Cerebral Cortex , 1985, Neurology.

[15]  D. Bar-Sagi,et al.  Microinjection of the ras oncogene protein into PC12 cells induces morphological differentiation , 1985, Cell.

[16]  A. Ogura,et al.  Sarcoma viruses carrying ras oncogenes induce differentiation-associated properties in a neuronal cell line , 1985, Nature.

[17]  D. Burstein,et al.  Activated N‐ras gene induces neuronal differentiation of PC12 rat pheochromocytoma cells , 1986, Journal of cellular physiology.

[18]  C. Cordon-Cardo,et al.  Expression of ras proto-oncogene proteins in normal human tissues. , 1987, Oncogene.

[19]  J. E. Vaughn,et al.  Fine structure of synaptogenesis in the vertebrate central nervous system. , 1989, Synapse.

[20]  James E. Vaughn,et al.  Review: Fine structure of synaptogenesis in the vertebrate central nervous system , 1989 .

[21]  A. Larkman.  Dendritic morphology of pyramidal neurones of the visual cortex of the rat: I. Branching patterns , 1991, The Journal of comparative neurology.

[22]  A. Larkman,et al.  Dendritic morphology of pyramidal neurones of the visual cortex of the rat: II. Parameter correlations , 1991, The Journal of comparative neurology.

[23]  R. Mervis,et al.  Exogenous Nerve Growth Factor Reverses Age‐Related Structural Changes in Neocortical Neurons in the Aging Rat , 1991, Annals of the New York Academy of Sciences.

[24]  P. Ernfors,et al.  Molecular cloning of rat trkC and distribution of cells expressing messenger RNAs for members of the trk family in the rat central nervous system , 1992, Neuroscience.

[25]  E. Nishida,et al.  The MAP kinase cascade is essential for diverse signal transduction pathways. , 1993, Trends in biochemical sciences.

[26]  Natalie G. Ahn,et al.  The MAP kinase cascade. Discovery of a new signal transduction pathway. , 1993 .

[27]  R. Heumann.  Neurotrophin signalling , 1994, Current Opinion in Neurobiology.

[28]  L. Phillips,et al.  Increase of c-fos and ras oncoproteins in the denervated neuropil of the rat dentate gyrus , 1994, Neuroscience.

[29]  Lawrence C. Katz,et al.  Neurotrophins regulate dendritic growth in developing visual cortex , 1995, Neuron.

[30]  R. Heumann,et al.  Induction of p21ras in Alzheimer pathology. , 1995, Neuroreport.

[31]  G. White,et al.  Benzodiazepine site inverse agonists can selectively inhibit subtypes of the GABAA receptor. , 1995, Neuroreport.

[32]  H. Thoenen.  Neurotrophins and Neuronal Plasticity , 1995, Science.

[33]  M. Radeke,et al.  Developmental and mature expression of full‐length and truncated TrkB, receptors in the rat forebrain , 1996, The Journal of comparative neurology.

[34]  Lawrence C Katz,et al.  Neurotrophin Regulation of Cortical Dendritic Growth Requires Activity , 1996, Neuron.

[35]  B. Kolb,et al.  Nerve growth factor treatment prevents dendritic atrophy and promotes recovery of function after cortical injury , 1997, Neuroscience.

[36]  Lawrence C. Katz,et al.  Opposing Roles for Endogenous BDNF and NT-3 in Regulating Cortical Dendritic Growth , 1997, Neuron.

[37]  Rodney A. Swain,et al.  Learning-Dependent Dendritic Hypertrophy of Cerebellar Stellate Cells: Plasticity of Local Circuit Neurons , 1997, Neurobiology of Learning and Memory.

[38]  M. Radeke,et al.  Immunocytochemical localization of TrkB in the central nervous system of the adult rat , 1997, The Journal of comparative neurology.

[39]  Y. Jan,et al.  Rho family GTP-binding proteins in growth cone signalling. , 1997, Current opinion in neurobiology.

[40]  B. Jacobs,et al.  Life‐span dendritic and spine changes in areas 10 and 18 of human cortex: A quantitative golgi study , 1997, The Journal of comparative neurology.

[41]  George Paxinos,et al.  The Mouse Brain in Stereotaxic Coordinates , 2001 .

[42]  Y. Jan,et al.  Rho family small GTP-binding proteins in growth cone signalling , 1997, Current Opinion in Neurobiology.

[43]  Paul W. Frankland,et al.  A mouse model for the learning and memory deficits associated with neurofibromatosis type I , 1997, Nature Genetics.

[44]  S. Grant,et al.  A role for the Ras signalling pathway in synaptic transmission and long-term memory , 1997, Nature.

[45]  B. Kolb,et al.  Nerve growth factor stimulates growth of cortical pyramidal neurons in young adult rats , 1997, Brain Research.

[46]  J. van Pelt,et al.  Growth of pyramidal, but not non‐pyramidal, dendrites in long‐term organotypic explants of neonatal rat neocortex chronically exposed to neurotrophin‐3 , 1998, The European journal of neuroscience.

[47]  Mnh,et al.  Histologie du Système Nerveux de Lʼhomme et des Vertébrés , 1998 .

[48]  R. A. Murphy,et al.  Activity-dependent activation of TrkB neurotrophin receptors in the adult CNS. , 1999, Learning & memory.

[49]  Stephen J. Smith.  Dissecting Dendrite Dynamics , 1999, Science.

[50]  U. Gärtner,et al.  Elevated expression of p21ras is an early event in Alzheimer's disease and precedes neurofibrillary degeneration , 1999, Neuroscience.

[51]  C. Holt,et al.  The Neuronal Architecture of Xenopus Retinal Ganglion Cells Is Sculpted by Rho-Family GTPases In Vivo , 1999, The Journal of Neuroscience.

[52]  L. C. Katz,et al.  Destabilization of Cortical Dendrites and Spines by BDNF , 1999, Neuron.

[53]  J. Adelman,et al.  ChIPping away at potassium channel regulation , 2000, Nature Neuroscience.

[54]  E. Wagner,et al.  Transgenic Activation of Ras in Neurons Promotes Hypertrophy and Protects from Lesion-Induced Degeneration , 2000, The Journal of cell biology.

[55]  A. Davies.  Neurotrophins: Neurotrophic modulation of neurite growth , 2000, Current Biology.

[56]  N. Spruston,et al.  Diversity and dynamics of dendritic signaling. , 2000, Science.

[57]  H. Cline,et al.  Rho GTPases regulate distinct aspects of dendritic arbor growth in Xenopus central neurons in vivo , 2000, Nature Neuroscience.

[58]  A. Yamashita,et al.  Development of full-length Trk B-immunoreactive structures in the prefrontal and visual cortices of the macaque monkey , 2000, Anatomy and Embryology.

[59]  D. Riddle,et al.  Insulin-Like Growth Factor I Stimulates Dendritic Growth in Primary Somatosensory Cortex , 2000, The Journal of Neuroscience.

[60]  Ann Y. Nakayama,et al.  Small GTPases Rac and Rho in the Maintenance of Dendritic Spines and Branches in Hippocampal Pyramidal Neurons , 2000, The Journal of Neuroscience.

[61]  B. Moore,et al.  Brain volume in children with neurofibromatosis type 1 , 2000, Neurology.

[62]  Y. Yamaguchi,et al.  Small GTPase RhoG Is a Key Regulator for Neurite Outgrowth in PC12 Cells , 2000, Molecular and Cellular Biology.

[63]  A. McAllister,et al.  Cellular and molecular mechanisms of dendrite growth. , 2000, Cerebral cortex.

[64]  Karl Deisseroth,et al.  Spaced stimuli stabilize MAPK pathway activation and its effects on dendritic morphology , 2001, Nature Neuroscience.

[65]  R. Heumann,et al.  Activation of mitogen-activated protein kinase cascade and phosphorylation of cytoskeletal proteins after neurone-specific activation of p21ras. I. Mitogen-activated protein kinase cascade , 2001, Neuroscience.

[66]  Liqun Luo,et al.  How do dendrites take their shape? , 2001, Nature Neuroscience.

[67]  R. Heumann,et al.  Activation of mitogen-activated protein kinase cascade and phosphorylation of cytoskeletal proteins after neurone-specific activation of p21ras. II. Cytoskeletal proteins and dendritic morphology , 2001, Neuroscience.

[68]  J. Jacobs,et al.  Regional dendritic and spine variation in human cerebral cortex: a quantitative golgi study. , 2001, Cerebral cortex.

[69]  Anirvan Ghosh,et al.  The role of Notch and Rho GTPase signaling in the control of dendritic development , 2001, Current Opinion in Neurobiology.

[70]  E. Huang,et al.  Neurotrophins: roles in neuronal development and function. , 2001, Annual review of neuroscience.

[71]  E. Feldman,et al.  Signaling mechanisms that regulate actin‐based motility processes in the nervous system , 2002, Journal of neurochemistry.

[72]  L. C. Katz,et al.  BDNF release from single cells elicits local dendritic growth in nearby neurons , 2002, Nature Neuroscience.

[73]  R. Wong,et al.  Activity-dependent regulation of dendritic growth and patterning , 2002, Nature Reviews Neuroscience.

[74]  J. Morrison,et al.  Quantitative analysis of the dendritic morphology of corticocortical projection neurons in the macaque monkey association cortex , 2002, Neuroscience.

[75]  A. McAllister.  Neurotrophins and cortical development. , 2002, Results and problems in cell differentiation.

[76]  K. Rockland,et al.  The pyramidal cell of the sensorimotor cortex of the macaque monkey: phenotypic variation. , 2002, Cerebral cortex.

[77]  Anirvan Ghosh,et al.  Molecular control of cortical dendrite development. , 2002, Annual review of neuroscience.

[78]  H. Katoh,et al.  Rho family GTPases as key regulators for neuronal network formation. , 2002, Journal of biochemistry.

[79]  H. Cline,et al.  Regulation of Rho GTPases by Crosstalk and Neuronal Activity In Vivo , 2002, Neuron.

[80]  M. L. Pucak,et al.  Dendritic morphology of callosal and ipsilateral projection neurons in monkey prefrontal cortex , 2002, Neuroscience.

[81]  E. Huang,et al.  Trk receptors: roles in neuronal signal transduction. , 2003, Annual review of biochemistry.

[82]  D. Slamon,et al.  Organ specific expression of ras oncoproteins during growth and development of the rat , 1986, Molecular and Cellular Biochemistry.

[83]  M. Feldman,et al.  Loss of dendritic spines in aging cerebral cortex , 1975, Anatomy and Embryology.

[84]  J. Wenzel,et al.  Morphological alterations of hippocampal pyramidal neurons heterotopically transplanted into the somatosensory cortex of adult rats: a quantitative Golgi study , 1995, Anatomy and Embryology.

[85]  N. Ahn.  The MAP kinase cascade. Discovery of a new signal transduction pathway , 2005, Molecular and Cellular Biochemistry.

[86]  T. Serwold,et al.  Dendrite growth increased by visual activity requires NMDA receptor and Rho GTPases , 2022 .