Pre-Target Axon Sorting Establishes the Neural Map Topography

Imai, Takeshi; Yamazaki, T.; Kobayakawa, Reiko; Kobayakawa, Ko; Abe, Takaya; Suzuki, Misao; Sakano, Hitoshi

doi:10.1126/science.1173596

Cited by 200 publications

(277 citation statements)

References 38 publications

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“…Altered cAMP signaling, in turn, results in transcriptional dysregulation of neuronal guidance proteins and may also affect locally the behavior of the growth cones in response to external repulsive or attractive cues. These results are in line with recent findings implicating cAMP in the regulation of axonal pathfinding (29,39) as well as dendrite formation (40) and provide strong support for altered (increased) neuronal cAMP signaling due to a bona fide SCHZ risk mutation. Notably, we have recently reported an association between SCHZ and gain of function mutations in the VIPR2 locus (41) and showed that these mutations also enhance cAMP signaling in lymphocytes of patients.…”

Section: Discussionsupporting

confidence: 90%

“…In summary, we showed that Disc1 Tm1Kara results in dysregulation of molecules involved in axon guidance and dendritic growth, whose expression is modulated by cAMP signals. Notably, the pattern of dysregulation is similar to the one reported previously in the olfactory system (29).…”

Section: Disc1 Tm1karasupporting

confidence: 85%

“…7A), raising the possibility that Disc1 Tm1Kara results in transcriptional alterations. In other systems, elevated cAMP levels have been associated with aberrant axonal targeting through CREB-mediated transcriptional regulation of key pathfinding molecules, including those molecules belonging to neuropilin/plexin/semaphorin signaling complexes (29). The axonal lamination phenotype observed in Disc1 Tm1Kara mutant mice and the fact that neuropilins and plexins have been extensively implicated in MF targeting, laminar-restricted positioning (30,31), and more recently, GC dendritic outgrowth (32) prompted us to assess their levels in the DG of Disc1 Tm1Kara mutant mice.…”

Section: Disc1 Tm1karamentioning

confidence: 99%

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Altered axonal targeting and short-term plasticity in the hippocampus of Disc1 mutant mice

Kvajo

McKellar

et al. 2011

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

106

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Carefully designed animal models of genetic risk factors are likely to aid our understanding of the pathogenesis of schizophrenia. Here, we study a mouse strain with a truncating lesion in the endogenous Disc1 ortholog designed to model the effects of a schizophreniapredisposing mutation and offer a detailed account of the consequences that this mutation has on the development and function of a hippocampal circuit. We uncover widespread and cumulative cytoarchitectural alterations in the dentate gyrus during neonatal and adult neurogenesis, which include errors in axonal targeting and are accompanied by changes in short-term plasticity at the mossy fiber/CA3 circuit. We also provide evidence that cAMP levels are elevated as a result of the Disc1 mutation, leading to altered axonal targeting and dendritic growth. The identified structural alterations are, for the most part, not consistent with the growthpromoting and premature maturation effects inferred from previous RNAi-based Disc1 knockdown. Our results provide support to the notion that modest disturbances of neuronal connectivity and accompanying deficits in short-term synaptic dynamics is a general feature of schizophrenia-predisposing mutations. psychiatric disease | rare mutation | mouse model T he schizophrenia (SCHZ) susceptibility gene DISC1 was identified through a balanced chromosomal translocation (1;11)(q42.1;q14.3) segregating with SCHZ and mood disorders in a large Scottish pedigree. This is the only confirmed disease risk allele within the DISC1 locus. The biology of DISC1 is being interrogated with a variety of approaches, such as acute RNAimediated gene knockdown (1-4), overexpression of truncated forms of the human DISC1 (5, 6), and chemical mutagenesis (7). Although they provide information about potential pathways related to DISC1, these approaches are not meant to recapitulate the integrated effects of the pathogenic translocation, and the relevance of these findings to SCHZ pathogenesis remains uncertain.We used a disease-focused knockin approach to introduce a truncating lesion in the endogenous murine Disc1 ortholog designed to model the effects of the (1;11) translocation (Mouse Genome Informatics nomenclature Disc1 Tm1Kara ) (8, 9). Although the divergence in the human and mouse Disc1 gene does not allow an exact replication of the human translocation, this mouse model approximates very closely the Scottish mutation. One advantage of our approach is that it retains endogenous levels as well as spatial and temporal patterns of Disc1 expression, and it preserves short N-terminal isoforms that are presumably unaffected by the Scottish translocation and seem to be expressed at relatively higher levels in the hippocampus (HPC) of patients with SCHZ (10). A comprehensive behavioral analysis has shown that Disc1 Tm1Kara mice display a unique profile of cognitive impairments, including specific and robust deficiencies in working memory (WM) tests (8, 9), which may relate to similar cognitive deficits prominent in psychotic disorders.DISC1 is...

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Section: Discussionsupporting

confidence: 90%

Section: Disc1 Tm1karasupporting

confidence: 85%

Section: Disc1 Tm1karamentioning

confidence: 99%

See 1 more Smart Citation

Altered axonal targeting and short-term plasticity in the hippocampus of Disc1 mutant mice

Kvajo

McKellar

et al. 2011

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

106

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“…The chemotactic cues hypothesized by Cajal would fall into this category. For example, Semaphorin3A acts as a secreted repellent that prevents entry of early arriving olfactory axons into the chick olfactory bulb (Luo et al 1993;Renzi et al 2000), or in the mouse olfactory system, helps to map sensory axons from the epithelium onto specific regions of the olfactory bulb (Schwarting et al 2000;Taniguchi et al 2003;Imai et al 2009). Netrin/ unc6 is a secreted chemotactic signal produced at the ventral midlines of both vertebrates and invertebrates.…”

Section: Tropic Guidance Cuesmentioning

confidence: 99%

Cellular Strategies of Axonal Pathfinding

Raper

Mason

2010

Cold Spring Harbor Perspectives in Biology

157

130

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Axons follow highly stereotyped and reproducible trajectories to their targets. In this review we address the properties of the first pioneer neurons to grow in the developing nervous system and what has been learned over the past several decades about the extracellular and cell surface substrata on which axons grow. We then discuss the types of guidance cues and their receptors that influence axon extension, what determines where cues are expressed, and how axons respond to the cues they encounter in their environment.T his article provides an overview of how growth cones respond to the cellular substrata and molecular cues they encounter as they extend through the developing nervous system. It elaborates on the primer by Kolodkin and TessierLavigne (2010) and touches on many of the topics covered in greater detail in the articles that follow. The first sections describe how axons extend in a directed manner, the substrata on which they grow, interactions between pioneer and follower axons, and growth cone behaviors in emerging tracts and at decision points. The subsequent sections discuss examples of specific cues, their distributions, how their distributions are determined, and how growth cones integrate multiple cues during pathfinding. AXONS EXTEND IN VIVO IN A DIRECTED MANNERThe first person to visualize the growing tips of axons, Ramon y Cajal, recognized that axons for the most part grow very efficiently towards their ultimate targets. He was a strong advocate for axons finding their way in response to chemotactic cues:"If one admits that neuroblasts are endowed with chemotactic properties, then one might also imagine that they are capable of ameboid movements, initiated by factors secreted from epithelial, neural, or mesodermal elements. As a result, their processes may be oriented in the direction of chemical gradients, and thus guided to the secreting cells" (Ramon y Cajal 1892; trans. English, 1995).This surprisingly modern outlook emphasizing directed guidance was temporarily derailed by the views of Weiss during the 1920s and 1930s. He first argued that functional specificity did not arise as a consequence of specific axonal connections (Weiss 1936), and later argued that nonspecific mechanical guidance cues play a predominant role in guiding axons and organizing them into nerves and tracts

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“…However, at the tissue level, the complex interconnectivity is masked by the distribution of neurons, such as in the stratified laminar layers of the neocortex. Although functionally related neurons generally group together (3,4), boundaries of functional units cannot be readily revealed with phenotype markers, necessitating electrophysiological studies and correlative functional outcomes. It is, therefore, necessary to differentiate physical and functional associations of neuronal populations to unravel complex networks.…”

mentioning

confidence: 99%

Bioengineered functional brain-like cortical tissue

Tang-Schomer¹,

White²,

Tien³

et al. 2014

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

260

299

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The brain remains one of the most important but least understood tissues in our body, in part because of its complexity as well as the limitations associated with in vivo studies. Although simpler tissues have yielded to the emerging tools for in vitro 3D tissue cultures, functional brain-like tissues have not. We report the construction of complex functional 3D brain-like cortical tissue, maintained for months in vitro, formed from primary cortical neurons in modular 3D compartmentalized architectures with electrophysiological function. We show that, on injury, this brain-like tissue responds in vitro with biochemical and electrophysiological outcomes that mimic observations in vivo. This modular 3D brain-like tissue is capable of real-time nondestructive assessments, offering previously unidentified directions for studies of brain homeostasis and injury.electrophysiology | connectivity | silk | scaffold | traumatic brain injury

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Pre-Target Axon Sorting Establishes the Neural Map Topography

Cited by 200 publications

References 38 publications

Altered axonal targeting and short-term plasticity in the hippocampus of Disc1 mutant mice

Altered axonal targeting and short-term plasticity in the hippocampus of Disc1 mutant mice

Cellular Strategies of Axonal Pathfinding

Bioengineered functional brain-like cortical tissue

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