Chemoaffinity Revisited: Dscams, Protocadherins, and Neural Circuit Assembly

Zipursky, S. Lawrence; Sanes, Joshua R.

doi:10.1016/j.cell.2010.10.009

Cited by 293 publications

(353 citation statements)

References 65 publications

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“…critical period | ocular dominance plasticity | silent synapse | PSD-95 | visual cortex I mmature cortical neural networks, which are formed primarily under genetic control (1), require experience and training to shape and optimize their functional properties. This experiencedependent refinement is considered to be a general developmental process for all functional cortical domains and typically peaks during their respective critical periods (CPs) (2,3).…”

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confidence: 99%

Progressive maturation of silent synapses governs the duration of a critical period

Huang

Stodieck

Goetze

et al. 2015

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

172

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During critical periods, all cortical neural circuits are refined to optimize their functional properties. The prevailing notion is that the balance between excitation and inhibition determines the onset and closure of critical periods. In contrast, we show that maturation of silent glutamatergic synapses onto principal neurons was sufficient to govern the duration of the critical period for ocular dominance plasticity in the visual cortex of mice. Specifically, postsynaptic density protein-95 (PSD-95) was absolutely required for experience-dependent maturation of silent synapses, and its absence before the onset of critical periods resulted in lifelong juvenile ocular dominance plasticity. Loss of PSD-95 in the visual cortex after the closure of the critical period reinstated silent synapses, resulting in reopening of juvenile-like ocular dominance plasticity. Additionally, silent synapse-based ocular dominance plasticity was largely independent of the inhibitory tone, whose developmental maturation was independent of PSD-95. Moreover, glutamatergic synaptic transmission onto parvalbumin-positive interneurons was unaltered in PSD-95 KO mice. These findings reveal not only that PSD-95-dependent silent synapse maturation in visual cortical principal neurons terminates the critical period for ocular dominance plasticity but also indicate that, in general, once silent synapses are consolidated in any neural circuit, initial experience-dependent functional optimization and critical periods end.

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mentioning

confidence: 99%

Progressive maturation of silent synapses governs the duration of a critical period

Huang

Stodieck

Goetze

et al. 2015

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

172

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“…We propose that CTCF and the cohesin complex initiate and maintain Pcdhα promoter choice by mediating interactions between Pcdhα promoters and enhancers. T he combinatorial expression of cell surface proteins generates single-cell diversity within populations of neurons, and this diversity can specify neuronal connectivity and mediate self-recognition and self-avoidance (1). Specialized genetic mechanisms have evolved to generate this diversity.…”

mentioning

confidence: 99%

Role of CCCTC binding factor (CTCF) and cohesin in the generation of single-cell diversity of Protocadherin-α gene expression

Monahan

Rudnick

Kehayova

et al. 2012

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

143

126

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Extraordinary single-cell diversity is generated in the vertebrate nervous system by the combinatorial expression of the clustered protocadherin genes (Pcdhα, -β, and -γ). This diversity is generated by a combination of stochastic promoter choice and alternative premRNA splicing. Here we show that both the insulator-binding protein CTCF and the cohesin complex subunit Rad21 bind to two highly conserved DNA sequences, the first within and the second downstream of transcriptionally active Pcdhα promoters. Both CTCF and Rad21 bind to these sites in vitro and in vivo, this binding directly correlates with alternative isoform expression, and knocking down CTCF expression reduces alternative isoform expression. Remarkably, a similarly spaced pair of CTCF/Rad21 binding sites was identified within a distant enhancer element (HS5-1), which is required for normal levels of alternative isoform expression. We also identify an additional, unique regulatory role for cohesin, as Rad21 binds to another enhancer (HS7) independently of CTCF, and knockdown of Rad21 reduces expression of the constitutive, biallelically expressed Pcdhα isoforms αc1 and αc2. We propose that CTCF and the cohesin complex initiate and maintain Pcdhα promoter choice by mediating interactions between Pcdhα promoters and enhancers.

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“…Given the similarities between Dscam1 and Pcdhs, they could conceivably function similarly in neuronal selfrecognition [11]. The striking findings of Lefebvre et al [13] have supported this view by pinpointing a role for Pcdhs in self-recognition and self-avoidance in mammalian neurons.…”

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confidence: 96%

“…Although mammalian Dscam participates in self-avoidance, it is unlikely to underlie discrimination of self and non-self since it does not undergo the same complex alternative splicing as Dscam1 in Drosophila. Alternatively, the clustered protocadherins (Pcdhs) have emerged as good candidate mediators of self identity in mammalian neurons [9][10][11]. Pcdhs are generated from a complex genetic locus in mice, consisting of Pcdh-α, Pcdh-β and Pcdh-γ, which encode 14, 22 and 22 variant proteins, respectively ( Figure 1) [10].…”

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confidence: 99%