Thalamocortical Axons Are Influenced by Chemorepellent and Chemoattractant Activities Localized to Decision Points along Their Path

Braisted, Janet E.; Tuttle, Rebecca; O’Leary, Dennis D.M.

doi:10.1006/dbio.1999.9216

Cited by 97 publications

(111 citation statements)

References 48 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: 47%

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: 47%

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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“…In contrast, in Robo2 mutants, some thalamocortical fibers were observed to fail reaching the telencephalon, and instead growing abnormally toward the ventral diencephalon, a region normally nonpermissive for thalamocortical axon outgrowth (n ϭ 4) (Fig. 4 I) (Braisted et al, 1999). DiI injections in the dorsal thalamus of control, Robo1 and Robo2 mutants confirmed that numerous thalamocortical axons failed to enter the telencephalon and instead invaded the hypothalamus in Robo2 mutants (Fig.…”

Section: Abnormal Corticospinal and Thalamocortical Projections Inmentioning

confidence: 87%

“…Several studies have examined the early development of these projections and have identified pioneering axonal populations as well as potential intermediate targets and choice points for these axons (McConnell et al, 1989;De Carlos and O'Leary, 1992;Métin and Godement, 1996;Molnár et al, 1998;Braisted et al, 1999;Tuttle et al, 1999;Auladell et al, 2000;Ló pez-Bendito et al, 2006). In addition, multiple molecules that participate in the guidance of these connections have been identified, providing a comprehensive frame in which to understand their development (Serafini et al, 1996;Métin et al, 1997;Richards et al, 1997;Braisted et al, 2000;Leighton et al, 2001;Bagri et al, 2002;Ló pez-Bendito et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Robo1 and Robo2 Cooperate to Control the Guidance of Major Axonal Tracts in the Mammalian Forebrain

López‐Bendito¹,

Flames²,

Ma³

et al. 2007

J. Neurosci.

205

209

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The function of the nervous system depends on the precision of axon wiring during development. Previous studies have demonstrated that Slits, a family of secreted chemorepellent proteins, are crucial for the proper development of several major forebrain tracts. Mice deficient in Slit2 or, even more so, in both Slit1 and Slit2 have defects in multiple axonal pathways, including corticofugal, thalamocortical, and callosal connections. In the spinal cord, members of the Robo family of proteins help mediate the function of Slits, but the relative contribution of these receptors to the guidance of forebrain projections remains to be determined. In the present study, we addressed the function of Robo1 and Robo2 in the guidance of forebrain projections by analyzing Robo1-, Robo2-, and Robo1;Robo2-deficient mice. Mice deficient in Robo2 and, more dramatically, in both Robo1 and Robo2, display prominent axon guidance errors in the development of corticofugal, thalamocortical, and corticocortical callosal connections. Our results demonstrate that Robo1 and Robo2 mostly cooperate to mediate the function of Slit proteins in guiding the major forebrain projections.

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“…For example, structures in the embryonic diencephalon and basal ganglia are implicated in providing signals that guide the growing axons, through attractants (Metin and Godement, 1996;Metin et al, 1997;Richards et al, 1997;Bagnard et al, 1998;Braisted et al, 1999;Braisted et al, 2000), repellents (Bagnard et al, 1998;Braisted et al, 1999;Bagri et al, 2002), or by producing pioneering axons (Mitrofanis and Guillery, 1993). In particular, groups of cells in the basal ganglia have been proposed to be intermediate targets for cortical and thalamic axons, by producing attractants or forming transient projections to the thalamus (Mitrofanis and Guillery, 1993;Metin and Godement, 1996;Tuttle et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

The early topography of thalamocortical projections is shifted inEbf1andDlx1/2mutant mice

Garel

Yun

Grosschedl³

et al. 2002

Development

108

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The prevailing model to explain the formation of topographic projections in the nervous system stipulates that this process is governed by information located within the projecting and targeted structures. In mammals, different thalamic nuclei establish highly ordered projections with specific neocortical domains and the mechanisms controlling the initial topography of these projections remain to be characterized. To address this issue, we examined Ebf1 -/-embryos in which a subset of thalamic axons does not reach the neocortex. We show that the projections that do form between thalamic nuclei and neocortical domains have a shifted topography, in the absence of regionalization defects in the thalamus or neocortex. This shift is first detected inside the basal ganglia, a structure on the path of thalamic axons, and which develops abnormally in Ebf1 -/-embryos. A similar shift in the topography of thalamocortical axons inside the basal ganglia and neocortex was observed in Dlx1/2 -/-embryos, which also have an abnormal basal ganglia development. Furthermore, Dlx1 and Dlx2 are not expressed in the dorsal thalamus or in cortical projections neurons. Thus, our study shows that: (1) different thalamic nuclei do not establish projections independently of each other; (2) a shift in thalamocortical topography can occur in the absence of major regionalization defects in the dorsal thalamus and neocortex; and (3) the basal ganglia may contain decision points for thalamic axons' pathfinding and topographic organization. These observations suggest that the topography of thalamocortical projections is not strictly determined by cues located within the neocortex and may be regulated by the relative positioning of thalamic axons inside the basal ganglia.

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Thalamocortical Axons Are Influenced by Chemorepellent and Chemoattractant Activities Localized to Decision Points along Their Path

Cited by 97 publications

References 48 publications

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

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

Robo1 and Robo2 Cooperate to Control the Guidance of Major Axonal Tracts in the Mammalian Forebrain

The early topography of thalamocortical projections is shifted inEbf1andDlx1/2mutant mice

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