Netrin-DCC Signaling Regulates Corpus Callosum Formation Through Attraction of Pioneering Axons and by Modulating Slit2-Mediated Repulsion

Fothergill, Thomas; Donahoo, Amber-Lee S.; Douglass, Amelia M.; Zalucki, Oressia; Yuan, Jiajia; Shu, Tianzhi; Goodhill, Geoffrey J.; Richards, Linda J.

doi:10.1093/cercor/bhs395

Cited by 95 publications

(122 citation statements)

References 55 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: 48%

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: 48%

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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“…Whether NRP2 functions as a compensatory factor in Emx1 −/− /C57Bl/6 mice is of interest for future study. In addition, we recently demonstrated that cingulate callosal axons also express the axon guidance receptor DCC, and that these axons are attracted towards its ligand, NTN1, at the midline (Fothergill et al, 2014). Similarly, other short-and longrange axon guidance molecules have been demonstrated to function in regulating neocortical callosal pathfinding (Shu and Richards, 2001;Shu et al, 2003;Andrews et al, 2006;Islam et al, 2009;Nishikimi et al, 2011).…”

Section: Emx1 Mediates Cingulate Callosal Axon Guidance By Regulatingmentioning

confidence: 95%

EMX1 regulates NRP1-mediated wiring of the mouse anterior cingulate cortex

et al. 2015

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Transcription factors act during cortical development as master regulatory genes that specify cortical arealization and cellular identities. Although numerous transcription factors have been identified as being crucial for cortical development, little is known about their downstream targets and how they mediate the emergence of specific neuronal connections via selective axon guidance. The EMX transcription factors are essential for early patterning of the cerebral cortex, but whether EMX1 mediates interhemispheric connectivity by controlling corpus callosum formation remains unclear. Here, we demonstrate that in mice on the C57Bl/6 background EMX1 plays an essential role in the midline crossing of an axonal subpopulation of the corpus callosum derived from the anterior cingulate cortex. In the absence of EMX1, cingulate axons display reduced expression of the axon guidance receptor NRP1 and form aberrant axonal bundles within the rostral corpus callosum. EMX1 also functions as a transcriptional activator of Nrp1 expression in vitro, and overexpression of this protein in Emx1 knockout mice rescues the midline-crossing phenotype. These findings reveal a novel role for the EMX1 transcription factor in establishing cortical connectivity by regulating the interhemispheric wiring of a subpopulation of neurons within the mouse anterior cingulate cortex.

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“…Loss of commissural inhibitory axonal connections of the corpus callosum might produce inappropriate bilateral activation of the sensorimotor cortex (Galléa et al, 2011;Lepage et al, 2012;Fothergill et al, 2013). Alternatively, inappropriate ipsilateral targeting of a subset of corticospinal tract axons could cause the behavioral deficits (Peng and Charron, 2013), consistent with unilateral motor cortex stimulation in DCC pa-tients producing bilateral motor activation (Cincotta et al, 2003;Depienne et al, 2011).…”

Section: Introductionmentioning

confidence: 98%

Mirror Movement-Like Defects in Startle Behavior of ZebrafishdccMutants Are Caused by Aberrant Midline Guidance of Identified Descending Hindbrain Neurons

et al. 2014

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Mirror movements are involuntary movements on one side of the body that occur simultaneously with intentional movements on the contralateral side. Humans with heterozygous mutations in the axon guidance receptor DCC display such mirror movements, where unilateral stimulation results in inappropriate bilateral motor output. Currently, it is unclear whether mirror movements are caused by incomplete midline crossing and reduced commissural connectivity of DCC-dependent descending pathways or by aberrant ectopic ipsilateral axonal projections of normally commissural neurons. Here, we show that in response to unilateral tactile stimuli, zebrafish dcc mutant larvae perform involuntary turns on the inappropriate body side. We show that these mirror movement-like deficits are associated with axonal guidance defects of two identified groups of commissural reticulospinal hindbrain neurons. Moreover, we demonstrate that in dcc mutants, axons of these identified neurons frequently fail to cross the midline and instead project ipsilaterally. Whereas laser ablation of these neurons in wild-type animals does not affect turning movements, their ablation in dcc mutants restores turning movements. Thus, our results demonstrate that in dcc mutants, turns on the inappropriate side of the body are caused by aberrant ipsilateral axonal projections, and suggest that aberrant ipsilateral connectivity of a very small number of descending axons is sufficient to induce incorrect movement patterns.

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Netrin-DCC Signaling Regulates Corpus Callosum Formation Through Attraction of Pioneering Axons and by Modulating Slit2-Mediated Repulsion

Cited by 95 publications

References 55 publications

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

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

EMX1 regulates NRP1-mediated wiring of the mouse anterior cingulate cortex

Mirror Movement-Like Defects in Startle Behavior of ZebrafishdccMutants Are Caused by Aberrant Midline Guidance of Identified Descending Hindbrain Neurons

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