Serum response factor controls neuronal circuit assembly in the hippocampus

Higher organisms rely on multiple modes of memory storage using the hippocampal network, which is built by precisely orchestrated mechanisms of axonal outgrowth, guidance and synaptic targeting. We demonstrate essential roles of the transcription factor serum response factor (SRF), a sensor of cytoskeletal actin dynamics, in all these processes. Conditional deletion of the mouse Srf gene reduced neurite outgrowth and abolished mossy fiber segregation, resulting in ectopic fiber growth inside the pyramidal layer. SRF-deficient mossy fibers aberrantly targeted CA3 somata for synapse formation. Axon guidance assays showed that SRF was a key mediator of ephrin-A and semaphorin guidance cues; in SRF-deficient neurons, these resulted in the formation of F-actin–microtubule rings rather than complete growth cone collapse. Dominant-negative variants of the SRF cofactor megakaryocytic acute leukemia (MAL) severely impeded neurite outgrowth and guidance. These data highlight essential links between SRF-mediated transcription and axon guidance and circuit formation in the hippocampus.

[1]  T. Blackstad,et al.  Special axo‐dendritic synapses in the hippocampal cortex: Electron and light microscopic studies on the layer of mossy fibers , 1961, The Journal of comparative neurology.

[2]  G. Bokoch,et al.  Nucleotide exchange factor GEF-H1 mediates cross-talk between microtubules and the actin cytoskeleton , 2002, Nature Cell Biology.

[3]  R. Treisman,et al.  The Rho family GTPases RhoA, Racl , and CDC42Hsregulate transcriptional activation by SRF , 1995, Cell.

[4]  J. Baraban,et al.  Nuclear translocation of the SRF co‐activator MAL in cortical neurons: role of RhoA signalling , 2005, Journal of neurochemistry.

[5]  C. Goodman,et al.  Semaphorins III and IV repel hippocampal axons via two distinct receptors. , 1998, Development.

[6]  Fan Wang,et al.  Neurotrophins and Netrins Require Calcineurin/NFAT Signaling to Stimulate Outgrowth of Embryonic Axons , 2003, Cell.

[7]  M. Frotscher,et al.  Neuronal migration in the murine rostral migratory stream requires serum response factor , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[8]  E. Dent,et al.  Cytoskeletal Dynamics and Transport in Growth Cone Motility and Axon Guidance , 2003, Neuron.

[9]  G. Yancopoulos,et al.  Mistargeting hippocampal axons by expression of a truncated Eph receptor , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[10]  M. Greenberg,et al.  Calcium Influx via the NMDA Receptor Induces Immediate Early Gene Transcription by a MAP Kinase/ERK-Dependent Mechanism , 1996, The Journal of Neuroscience.

[11]  R. Prywes,et al.  Myocardin/MKL family of SRF coactivators: Key regulators of immediate early and muscle specific gene expression , 2004, Journal of cellular biochemistry.

[12]  Y. Zou,et al.  Neuropilin-2 Regulates the Development of Select Cranial and Sensory Nerves and Hippocampal Mossy Fiber Projections , 2000, Neuron.

[13]  M. Tessier-Lavigne,et al.  Plexin-A3 Mediates Semaphorin Signaling and Regulates the Development of Hippocampal Axonal Projections , 2001, Neuron.

[14]  Richard Treisman,et al.  Isolation and properties of cDNA clones encoding SRF, a transcription factor that binds to the c-fos serum response element , 1988, Cell.

[15]  P. Rørth,et al.  Evidence for tension-based regulation of Drosophila MAL and SRF during invasive cell migration. , 2004, Developmental cell.

[16]  Thomas Lemberger,et al.  SRF mediates activity-induced gene expression and synaptic plasticity but not neuronal viability , 2005, Nature Neuroscience.

[17]  I. Black,et al.  Multiple ephrins regulate hippocampal neurite outgrowth , 2000 .

[18]  Ian D. Thompson,et al.  Opposing Gradients of Ephrin-As and EphA7 in the Superior Colliculus Are Essential for Topographic Mapping in the Mammalian Visual System , 2005, Neuron.

[19]  K. Murai,et al.  Control of hippocampal dendritic spine morphology through ephrin-A3/EphA4 signaling , 2003, Nature Neuroscience.

[20]  R. Nicoll,et al.  Contrasting properties of two forms of long-term potentiation in the hippocampus , 1995, Nature.

[21]  A. Nordheim,et al.  Serum response factor is crucial for actin cytoskeletal organization and focal adhesion assembly in embryonic stem cells , 2002, The Journal of cell biology.

[22]  Elena B. Pasquale,et al.  Eph receptor signalling casts a wide net on cell behaviour , 2005, Nature Reviews Molecular Cell Biology.

[23]  Da-Zhi Wang,et al.  Control of smooth muscle development by the myocardin family of transcriptional coactivators. , 2004, Current opinion in genetics & development.

[24]  W. Witke,et al.  RhoA/ROCK regulation of neuritogenesis via profilin IIa–mediated control of actin stability , 2003, The Journal of cell biology.

[25]  D. C. Sterio.  The unbiased estimation of number and sizes of arbitrary particles using the disector , 1984, Journal of microscopy.

[26]  A. Hall,et al.  Rho GTPases in cell biology , 2002, Nature.

[27]  M. Frotscher,et al.  Synaptic vesicle protein synaptoporin is differently expressed by subpopulations of mouse hippocampal neurons , 2002, The Journal of comparative neurology.

[28]  M. Kiebler,et al.  Chemically controlled formation of a DNA/calcium phosphate coprecipitate: application for transfection of mature hippocampal neurons. , 2004, Journal of neurobiology.

[29]  A. Wittinghofer,et al.  Modulation of NMDA Receptor— Dependent Calcium Influx and Gene Expression Through EphB Receptors , 2002 .

[30]  L. Van Aelst,et al.  The role of the Rho GTPases in neuronal development. , 2005, Genes & development.

[31]  P. Gass,et al.  Impaired fetal T cell development and perinatal lethality in mice lacking the cAMP response element binding protein. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[32]  H. J. G. Gundersen,et al.  The impact of recent stereological advances on quantitative studies of the nervous system , 1986, Journal of Neuroscience Methods.

[33]  T. Lemberger,et al.  A CamKIIalpha iCre BAC allows brain-specific gene inactivation. , 2001, Genesis.

[34]  Christofer Toumazou,et al.  A non-invasive approach to the bionic eye , 2008 .

[35]  Antje Gohla,et al.  Chronophin, a novel HAD-type serine protein phosphatase, regulates cofilin-dependent actin dynamics , 2005, Nature Cell Biology.

[36]  J. Kluger.  REWIRING THE BRAIN , 2006, Science.

[37]  A. Nordheim,et al.  Serum response factor is essential for mesoderm formation during mouse embryogenesis , 1998, The EMBO journal.

[38]  A. Nordheim,et al.  Generation of mice carrying conditional knockout alleles for the transcription factor SRF , 2002, Genesis.

[39]  T. Uemura,et al.  Control of Actin Reorganization by Slingshot, a Family of Phosphatases that Dephosphorylate ADF/Cofilin , 2002, Cell.

[40]  C. Dieterich,et al.  The SRF target gene Fhl2 antagonizes RhoA/MAL-dependent activation of SRF. , 2004, Molecular cell.

[41]  John G Flanagan,et al.  Retinal Axon Response to Ephrin-As Shows a Graded, Concentration-Dependent Transition from Growth Promotion to Inhibition , 2004, Neuron.

[42]  Richard Treisman,et al.  Signal-Regulated Activation of Serum Response Factor Is Mediated by Changes in Actin Dynamics , 1999, Cell.

[43]  M. Greenberg,et al.  EphA Receptors Regulate Growth Cone Dynamics through the Novel Guanine Nucleotide Exchange Factor Ephexin , 2001, Cell.

[44]  Margaret Fahnestock,et al.  Kindling and status epilepticus models of epilepsy: rewiring the brain , 2004, Progress in Neurobiology.

[45]  B. Wasylyk,et al.  Ets ternary complex transcription factors. , 2004, Gene.

[46]  Wim E Crusio,et al.  Using genetically-defined rodent strains for the identification of hippocampal traits relevant for two-way avoidance behavior: a non-invasive approach , 1989, Experientia.

[47]  A. Riccio,et al.  Apoptosis, Axonal Growth Defects, and Degeneration of Peripheral Neurons in Mice Lacking CREB , 2002, Neuron.

[48]  B. Heimrich,et al.  Infrapyramidal mossy fibers and two-way avoidance learning: developmental modification of hippocampal circuitry and adult behavior of rats and mice , 1988, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[49]  R. Treisman,et al.  Actin Dynamics Control SRF Activity by Regulation of Its Coactivator MAL , 2003, Cell.

[50]  M. Tessier-Lavigne,et al.  Stereotyped Pruning of Long Hippocampal Axon Branches Triggered by Retraction Inducers of the Semaphorin Family , 2003, Cell.

[51]  S. Offermanns,et al.  Plexin-B1 Directly Interacts with PDZ-RhoGEF/LARG to Regulate RhoA and Growth Cone Morphology , 2002, Neuron.

[52]  A. Püschel,et al.  The sequential activity of the GTPases Rap1B and Cdc42 determines neuronal polarity , 2004, Nature Neuroscience.