Netrin-1 Promotes Thalamic Axon Growth and Is Required for Proper Development of the Thalamocortical Projection

Braisted, Janet E.; Catalano, Susan M.; Stimac, Robert M.; Kennedy, Timothy E.; Tessier‐Lavigne, Marc; Shatz, Carla J.; O’Leary, Dennis D.M.

doi:10.1523/jneurosci.20-15-05792.2000

Cited by 181 publications

(170 citation statements)

References 28 publications

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“…In retinotectal axon branching, DCC mediates the netrin-1-induced branch-promoting signal (55). Similarly, growth of TC and callosal axons at the embryonic stages is promoted by netrin-DCC signaling (56)(57)(58)(59). However, the present data show that DCC is not strongly expressed in the thalamus at P14, and its binding to NTN4 is substantially weaker than that of Unc5B (Fig.…”

Section: Discussioncontrasting

confidence: 46%

Netrin-4 regulates thalamocortical axon branching in an activity-dependent fashion

Hayano

Sasaki

Ohmura

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Axon branching is remodeled by sensory-evoked and spontaneous neuronal activity. However, the underlying molecular mechanism is largely unknown. Here, we demonstrate that the netrin family member netrin-4 (NTN4) contributes to activity-dependent thalamocortical (TC) axon branching. In the postnatal developmental stages of rodents, ntn4 expression was abundant in and around the TC recipient layers of sensory cortices. Neuronal activity dramatically altered the ntn4 expression level in the cortex in vitro and in vivo. TC axon branching was promoted by exogenous NTN4 and suppressed by depletion of the endogenous protein. Moreover,, which strongly bound to NTN4, was expressed in the sensory thalamus, and knockdown of Unc5B in thalamic cells markedly reduced TC axon branching. These results suggest that NTN4 acts as a positive regulator for TC axon branching through activity-dependent expression.A xon branching is an essential process to determine the final pattern of neuronal connections. Previous studies have demonstrated that axon branching is controlled not only by axon guidance-related molecules (1-6) but also by neuronal activity, such as firing and synaptic activity (7-10). However, how neuronal activity is converted into the molecular signals that underlie axon branching is still largely unknown.The thalamocortical (TC) projection is a well-characterized system in which to address this issue. TC axons originating from sensory thalamic nuclei form elaborate arbors, primarily in layer 4 of the neocortex (11). Lamina-specific axon branching occurs from the onset of development and is universal in the mammalian cortex (12-17), indicating that a rigid developmental program is predominant for laminar specificity. TC axon branching is also known to be modified by neuronal activity. In the visual system, geniculocortical axon arbors can be remodeled drastically by manipulating visual experience and cortical-cell activity (18)(19)(20)(21)(22). A similar feature has been demonstrated in the somatosensory system. In mutant mice in which synaptic transmission or downstream signaling mechanisms are disrupted, TC axon arbors are affected primarily along the tangential axis whereas their laminar pattern is not obviously influenced (23-26). We have also shown in vitro that the loss of firing and synaptic activities substantially suppresses TC axon branching in the target layer (27). All of these findings imply the existence of a target-derived, branch-promoting molecule whose expression is regulated by neuronal activity. In this study, we attempted to identify this hypothetical molecule and to reveal the molecular mechanism of its action. Results Identification of a Target-Derived Molecule Whose Expression IsRegulated by Neural Activity. Because we have shown previously that spontaneous activity promotes TC axon branching in cocultures of the thalamus and cortex (27, 28), we attempted to identify gene(s) whose expression is down-regulated in corticalslice cultures by blocking firing and synaptic activity. Based on prior mole...

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Section: Discussioncontrasting

confidence: 46%

Netrin-4 regulates thalamocortical axon branching in an activity-dependent fashion

Hayano

Sasaki

Ohmura

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Netrin1 and netrin2, although not members of neurotrophin family per se, play important roles in axon growth and cell migration, and thus, are also relevant to cortical development. 22 We then determined the expression of these mRNAs in single DNs and GCs microdissected from tubers in an attempt to define the cellular specificity of these mRNA changes. Although the phenotypic distinctions between these cells remain a source of debate, we attempted to devise a strategy to classify these cells based on size and morphology.…”

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confidence: 99%

Differential Cellular Expression of Neurotrophins in Cortical Tubers of the Tuberous Sclerosis Complex

Kyin

Yang

Baybis

et al. 2001

The American Journal of Pathology

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Neurotrophins and their receptors modulate cerebral cortical development. Tubers in the tuberous sclerosis complex (TSC) are characterized histologically by disorganized cortical cytoarchitecture and thus, we hypothesized that expression of neurotrophin mRNAs and proteins might be altered in tubers. Using in situ transcription and mRNA amplification to probe cDNA arrays, we found that neurotrophin-3 (NT3) and trkB mRNA expression were reduced whereas neurotrophin-4 (NT4) and trkC mRNA expression were increased in whole tuber sections. Alterations in mRNA abundance were defined in single microdissected dysplastic neurons (DNs) and giant cells (GCs). NT3 mRNA expression was reduced in GCs and trkB mRNA expression was reduced in DNs. NT4 mRNA expression was increased in DNs and trkC mRNA expression was increased in both DNs and GCs. In three patients, TSC2 locus mutations were confirmed and the mean tuberin mRNA expression levels was reduced across all nine cases. Consistent with these observations, NT3 mRNA expression was reduced but trkC mRNA expression was increased in vitro in human NTera2 neurons ( Tubers in the tuberous sclerosis complex (TSC) are developmental abnormalities of cerebral cortical cytoarchitecture that are associated clinically with epilepsy. [1][2][3] Electrocorticography has shown that tubers are epileptogenic and seizures in TSC patients are often medically intractable despite anticonvulsant polytherapy. 4 -6 TSC is an autosomal-dominant disorder resulting from mutations in one of two genes, TSC1 or TSC2 7,8 although the mechanism by which mutations in either TSC gene leads to tuber formation is unknown. Disorganized cortical lamination and aberrant cellular morphology are important histological features of tubers. Large dysplastic neurons (DNs) and giant cells (GCs) are prominent cell types in tubers. 9 DNs and GCs share select morphological features including cytomegaly, the extension of aberrant processes often of unclear identity, ie, axons versus dendrites, and the expression of neural protein markers such as neurofilament and ␣-internexin. 1,9,10 The TSC2 knockout mouse 11 and the Eker rat strain 12 do not fully model human brain pathology in TSC, and thus, analysis of human tuber specimens provides the only direct avenue to study the mechanisms of tuber formation. One strategy to investigate the molecular pathogenesis of cytoarchitectural disorganization in tubers is to evaluate the expression of candidate genes and proteins in human tuber specimens that are relevant to cortical development. 10 Neurotrophins and their cognate receptors comprise a family of proteins that mediate proliferation, differentiation, migration, and process outgrowth during cortical development, 13,14 and thus, are ideal candidate molecules to investigate in tubers. Brainderived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4) exert their effects on neurons by binding selectively to a family of neuronal cell membrane receptors, trks A to C. 13,14 NGF signals...

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“…The five steps in the trajectory of growing thalamocortical and corticothalamic fibers as described in the text. The expression of guidance molecules is related to each of these steps: Slit (Bagri et al, 2002) to the emergence of thalamic axons out of the diencephalon and in the ventral telencephalon, an ephrin-A5 gradient in the ventral telencephalon for axonal presorting, Netrin-1 as an attractive factor for both populations in the internal capsule (Braisted et al, 2000), semaphorins 3A and 3C for cortical fibers to penetrate the intermediate zone (Bagnard et al, 1998), and EphA4 in the thalamus and ephrin-A5 in the cortex for the establishment of topographic connections Mackarehtschian et al, 1999;Vanderhaeghen et al, 2000). Th, thalamus; Hyp, hypothalamus; IC, internal capsule; GE, ganglionic eminence; Ncx, neocortex.…”

Section: A Small Step For An Axon a Giant Leap For Brain Circuitrymentioning

confidence: 99%

“…in the hypothalamus (Braisted et al, 1999;Bagri et al, 2002) and ganglionic eminences (Metin and Godement, 1996;Braisted et al, 1999Braisted et al, , 2000Bagri et al, 2002). This hypothesis is strongly supported by studies of the thalamocortical pathway in mutant mice strains (ebf1, dlx1, and dlx2 knockouts) with abnormal ganglionic eminences.…”

Section: A Small Step For An Axon a Giant Leap For Brain Circuitrymentioning

confidence: 99%

Connecting thalamus and cortex: The role of ephrins

et al. 2006

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The complex task of wiring up the brain during embryonic development is achieved by a multitude of guidance signals acting in complex combinations to drive growing axons to their proper targets. The somatosensory system provides an extensively studied model system featuring many universal mechanisms of neural development. In rodents, it constitutes an important model to study how precise topographic connections are achieved. Recent evidence suggests that the Eph/ephrin family of guidance molecules is of pivotal importance for the development of the somatosensory system. Members of Eph/ephrin family are thought to be involved in the global presorting of thalamic axons projecting to the cortex, in labeling specific cortical areas for innervation, in providing topographic cues within the target area, and in distinguishing cortical layers for intracortical wiring. The Eph/ephrin system also seems to contribute to the formation of specific corticothalamic feedback projections. So far, the functions of only a few members of the Eph/ephrin family have been examined, but expression analysis indicates complex combinatorial effects of these signaling molecules. Understanding the Eph/ephrin wiring code is expected to yield new insights into the development and plasticity of brain circuits involved in higher functions.

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Netrin-1 Promotes Thalamic Axon Growth and Is Required for Proper Development of the Thalamocortical Projection

Cited by 181 publications

References 28 publications

Netrin-4 regulates thalamocortical axon branching in an activity-dependent fashion

Netrin-4 regulates thalamocortical axon branching in an activity-dependent fashion

Differential Cellular Expression of Neurotrophins in Cortical Tubers of the Tuberous Sclerosis Complex

Connecting thalamus and cortex: The role of ephrins

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