The Rac1-GEF Tiam1 Couples the NMDA Receptor to the Activity-Dependent Development of Dendritic Arbors and Spines

506

461

Activity-regulated gene expression is believed to play a key role in the development and refinement of neuronal circuitry. Nevertheless, the transcriptional networks that regulate synapse growth and plasticity remain largely uncharacterized. Here, we show that microRNA 132 (miR132) is an activity-dependent rapid response gene regulated by the cAMP response element-binding (CREB) protein pathway. Introduction of miR132 into hippocampal neurons enhanced dendrite morphogenesis whereas inhibition of miR132 by 2 O-methyl RNA antagonists blocked these effects. Furthermore, neuronal activity inhibited translation of p250GAP, a miR132 target, and siRNA-mediated knockdown of p250GAP mimicked miR132-induced dendrite growth. Experiments using dominant-interfering mutants suggested that Rac signaling is downstream of miR132 and p250GAP. We propose that the miR132-p250GAP pathway plays a key role in activity-dependent structural and functional plasticity.cAMP response element-binding (CREB) protein ͉ transcription ͉ CaM kinase ͉ actin cytoskeleton ͉ Rac N euronal activity regulates the development and modification of neuronal circuitry in part by activating genetic programs. Activity-regulated gene expression has been implicated in axon guidance, dendrite elaboration, synapse formation, and long-lasting synaptic plasticity (1, 2). Dendrites are the primary site of excitatory synapses, and their morphogenesis determines both the size and number of synaptic contacts (3). Although dendritic development is partly controlled by intrinsic factors, neuronal activity also plays a critical role. Indeed, the timing of afferent innervation and synapse formation coincides with the period of maximum growth and dendritic remodeling (3).The transcription factor cAMP response element-binding (CREB) protein is a key regulator of dendritic growth (4) and activity-regulated dendritic refinement in mature neurons (5). Although CREB is believed to be a critical regulator of neuronal plasticity, few CREB targets have been directly linked to plasticity. To identify these genes, we developed a novel technology, termed serial analysis of chromatin occupancy (SACO) that facilitated the genome-wide identification of CREB target regions (6). We focused on microRNAs (miRNAs) because the ability of these molecules to repress gene expression is believed to play an important role in development, differentiation, proliferation, survival, and oncogenesis (7). Interestingly, a significant fraction of miRNAs are enriched or specifically expressed in the nervous system (8), and transcription of some miRNAs changes dynamically during brain development (9, 10). miRNAs have been implicated in development of neuronal asymmetry in Caenorhabditis elegans, maturation of sensory neurons in Drosophila, and neurite outgrowth and spine homeostasis in rodents (11)(12)(13)(14). Although activity is believed to play an essential role in sculpting neuronal development, miRNAs induced by neuronal activity have not been described.Here, we show that microRNA 132 (miR132) is an a...

Section: Discussionmentioning

confidence: 99%

An activity-regulated microRNA controls dendritic plasticity by down-regulating p250GAP

Wayman

Davare

Ando³

et al. 2008

506

461

“…In contrast with several previously identified signaling molecules, ␣1-chimaerin contributes to pruning rather than elaboration of dendrites. For example, the NR2B-associated Rac-GTP exchange factor (GEF) Tiam1 leads to Rac activation and spine growth in response to NMDA-receptor stimulation (14). Two other previously characterized GEFs, kallirin and intersectin, are recruited by EphB receptors, activate Rac and Cdc42, and thereby promote the formation of dendritic protrusions (25)(26)(27).…”

Section: Discussionmentioning

confidence: 99%

“…GEFs activate GTPases by promoting GDP-GTP exchange, whereas GAPs stimulate GTP hydrolysis and thereby inactivate Rho GTPases. In developing neurons such GTPase regulators appear to be ideal candidate molecules for linking neurotransmitter receptor signaling to alterations in Rho protein activity (13,14).…”

mentioning

confidence: 99%

The diacylglycerol-binding protein α1-chimaerin regulates dendritic morphology

Buttery

Beg

Chih

et al. 2006

The morphological and functional differentiation of neuronal dendrites is controlled through transcriptional programs and cell-cell signaling. Synaptic activity is thought to play an important role in the maturation of dendritic arbors, but the signaling pathways that couple neuronal activity and morphological changes in dendrites are not well understood. We explored the function of ␣1-chimaerin, a neuronal diacylglycerol-binding protein with a Rho GTPaseactivating protein domain that inactivates Rac1. We find that stimulation of phospholipase C␤-coupled cell surface receptors recruits ␣1-chimaerin to the plasma membrane of cultured hippocampal neurons. We further show that ␣1-chimaerin protein levels are controlled by synaptic activity and that increased ␣1-chimaerin expression results in the pruning of dendritic spines and branches. This pruning activity requires both the diacylglycerolbinding and Rac GTPase-activating protein activity of ␣1-chimaerin. Suppression of ␣1-chimaerin expression resulted in increased process growth from the dendritic shaft and from spine heads. Our data suggest that ␣1-chimaerin is an activity-regulated Rho GTPase regulator that is activated by phospholipase C␤-coupled cell surface receptors and contributes to pruning of dendritic arbors.spine ͉ neuronal activity ͉ phospholipase C ͉ pruning

“…We noted that Tiam1 is located within growth cones and promotes the formation of axons (14,15). The NMDA receptor controls the growth and morphological changes of dendritic arbors and spines through Tiam1-dependent Rac1 activation (16). These reports create interest in a role for this GEF in mediating neurotrophin actions on the cytoskeleton.…”

mentioning

confidence: 92%

TrkB binds and tyrosine-phosphorylates Tiam1, leading to activation of Rac1 and induction of changes in cellular morphology

Miyamoto

Yamauchi

Tanoue

et al. 2006

135

132

Small GTPases of the Rho family play key roles in the formation of neuronal axons and dendrites by transducing signals from guidance cues, such as neurotrophins, to the actin cytoskeleton. However, there is little insight into the mechanism by which neurotrophins regulate Rho GTPases. Here, we show the crucial role of the ubiquitous Rac1-specific guanine nucleotide exchange factor, Tiam1 (T lymphoma invasion and metastasis 1), in transducing a neurotrophin-mediated change in cell shape. We demonstrate that BDNF, acting through TrkB, directly binds and specifically activates Tiam1 by phosphorylating Tyr-829, leading to Rac1 activation and lamellipodia formation in Cos-7 cells and increased neurite outgrowth from cortical neurons. A point mutation in Tiam1, Tyr-829 to Phe-829, blocked these BDNF-induced changes in cellular morphology. The findings are evidence of a previously uncharacterized mechanism for the activation of Tiam1 and of a role for this effector in neurotrophin-mediated signal transduction leading to changes in cellular morphology.actin ͉ cortical neuron ͉ neurotrophin ͉ Rho guanine nucleotide exchange factors ͉ Rho GTPases