Spontaneous activity regulates Robo1 transcription to mediate a switch in thalamocortical axon growth

Mire, Erik; Mezzera, Cecilia; Leyva-Díaz, Eduardo; Paternain, Ana V.; Squarzoni, Paola; Bluy, Lisa; Castillo-Paterna, Mar; López, María José Rodrigo; Peregrín, Sandra; Tessier‐Lavigne, Marc; Garel, Sonia; Galcerán, Joan; Lerma, Juan; López‐Bendito, Guillermina

doi:10.1038/nn.3160

Cited by 79 publications

(92 citation statements)

References 52 publications

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“…activity is a key modulator of the growth rate of developing TCAs [4]. Robo1 acts as a brake for axonal growth, and its expression is upregulated in silenced thalamocortical neurons [4].…”

Section: +mentioning

confidence: 99%

“…Robo1 acts as a brake for axonal growth, and its expression is upregulated in silenced thalamocortical neurons [4]. However, the efficient regulation of axon growth speed might not only rely on the function of a brake but also on that of an accelerator.…”

Section: +mentioning

confidence: 99%

“…Thus, we investigated whether other genes regulated by spontaneous thalamic activity also modulate the growth rate of TCAs. To identify additional candidate genes involved in axon growth and that might be regulated by spontaneous activity, we overexpressed the inwardly rectifying potassium channel Kir2.1 (Kir) in thalamic neurons which will provoke hyperpolarization and dampening of neural activity [4,[20][21][22][23][24]. Dissociated thalamic cells were transfected with plasmids expressing Kir2.1 (Kir) and/or Gfp, and they were analyzed after 72 h in culture ( Fig 1A).…”

Section: +mentioning

confidence: 99%

“…The data are presented as the means AE s.e.m. Spontaneous thalamic activity regulates Robo1 and DCC levels in an opposite manner [4] (Fig 1). Silencing spontaneous activity increases Robo1 mRNA and protein, while it decreases DCC protein and mRNA.…”

Section: Activity-dependent Regulation Of DCC In Controlling Tca Growthmentioning

confidence: 99%

“…Thus, the course of axon growth is a tightly controlled process. Using the thalamocortical system as a model, we previously identified a mechanism that regulates the growth rate of developing axons [4]. We demonstrated that spontaneous Ca 2+ activity modulates axonal growth through the transcriptional upregulation of the guidance receptor Robo1, which appears to function as a brake for thalamocortical axon (TCA) growth [4].…”

Section: Introductionmentioning

confidence: 99%

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DCC functions as an accelerator of thalamocortical axonal growth downstream of spontaneous thalamic activity

et al. 2015

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Controlling the axon growth rate is fundamental when establishing brain connections. Using the thalamocortical system as a model, we previously showed that spontaneous calcium activity influences the growth rate of thalamocortical axons by regulating the transcription of Robo1 through an NF-jB-binding site in its promoter. Robo1 acts as a brake on the growth of thalamocortical axons in vivo. Here, we have identified the Netrin-1 receptor DCC as an accelerator for thalamic axon growth. Dcc transcription is regulated by spontaneous calcium activity in thalamocortical neurons and activating DCC signaling restores normal axon growth in electrically silenced neurons. Moreover, we identified an AP-1-binding site in the Dcc promoter that is crucial for the activity-dependent regulation of this gene. In summary, we have identified the Dcc gene as a novel downstream target of spontaneous calcium activity involved in axon growth. Together with our previous data, we demonstrate a mechanism to control axon growth that relies on the activity-dependent regulation of two functionally opposed receptors, Robo1 and DCC. These two proteins establish a tight and efficient means to regulate activity-guided axon growth in order to correctly establish neuronal connections during development.

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“…activity is a key modulator of the growth rate of developing TCAs [4]. Robo1 acts as a brake for axonal growth, and its expression is upregulated in silenced thalamocortical neurons [4].…”

Section: +mentioning

confidence: 99%

Section: +mentioning

confidence: 99%

Section: +mentioning

confidence: 99%

Section: Activity-dependent Regulation Of DCC In Controlling Tca Growthmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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DCC functions as an accelerator of thalamocortical axonal growth downstream of spontaneous thalamic activity

et al. 2015

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Neocortical arealization: Evolution, mechanisms, and open questions

Alfano

Studer

2013

Developmental Neurobiology

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The mammalian neocortex is a structure with no equals in the vertebrates and is the seat of the highest cerebral functions, such as thoughts and consciousness. It is radially organized into six layers and tangentially subdivided into functional areas deputed to the elaboration of sensory information, association between different stimuli, and selection and triggering of voluntary movements. The process subdividing the neocortical field into several functional areas is called "arealization". Each area has its own cytoarchitecture, connectivity, and peculiar functions. In the last century, several neuroscientists have investigated areal structure and the mechanisms that have led during evolution to the rising of the neocortex and its organization. The extreme conservation in the positioning and wiring of neocortical areas among different mammalian families suggests a conserved genetic program orchestrating neocortical patterning. However, the impressive plasticity of the neocortex, which is able to rewire and reorganize areal structures and connectivity after impairments of sensory pathways, argues for a more complex scenario. Indeed, even if genetics and molecular biology helped in identifying several genes involved in the arealization process, the logic underlying the neocortical bauplan is still beyond our comprehension. In this review, we will introduce the present knowledge and hypotheses on the ontogenesis and evolution of neocortical areas. Then, we will focus our attention on some open issues, which are still unresolved, and discuss some recent studies that might open new directions to be explored in the next few years.

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Thalamic neuronal specification and early circuit formation

Gezelius

López‐Bendito

2016

Developmental Neurobiology

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The thalamus is a central structure of the brain, primarily recognized for the relay of incoming sensory and motor information to the cerebral cortex but also key in high order intracortical communication. It consists of glutamatergic projection neurons organized in several distinct nuclei, each having a stereotype connectivity pattern and functional roles. In the adult, these nuclei can be appreciated by architectural boundaries, although their developmental origin and specification is only recently beginning to be revealed. Here, we summarize the current knowledge on the specification of the distinct thalamic neurons and nuclei, starting from early embryonic patterning until the postnatal days when active sensory experience is initiated and the overall system connectivity is already established. We also include an overview of the guidance processes important for establishing thalamocortical connections, with emphasis on the early topographical specification. The extensively studied thalamocortical axon branching in the cortex is briefly mentioned; however, the maturation and plasticity of this connection are beyond the scope of this review. In separate chapters, additional mechanisms and/or features that influence the specification and development of thalamic neurons and their circuits are also discussed. Finally, an outlook of future directions is given. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 830-843, 2017.

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Spontaneous activity regulates Robo1 transcription to mediate a switch in thalamocortical axon growth

Cited by 79 publications

References 52 publications

DCC functions as an accelerator of thalamocortical axonal growth downstream of spontaneous thalamic activity

DCC functions as an accelerator of thalamocortical axonal growth downstream of spontaneous thalamic activity

Neocortical arealization: Evolution, mechanisms, and open questions

Thalamic neuronal specification and early circuit formation

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