Pcdhαc2 is required for axonal tiling and assembly of serotonergic circuitries in mice

Chen, Weisheng V.; Nwakeze, Chiamaka L.; Denny, Christine A.; O’Keeffe, Sean; Rieger, Michael A.; Mountoufaris, George; Kirner, Amy; Dougherty, Joseph D.; Hen, René; Wu, Qiang; Maniatis, Tom

doi:10.1126/science.aal3231

Cited by 137 publications

(163 citation statements)

References 48 publications

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“…For example, recent studies have shown that unique interaction of PcdhγC3 with Axin1 inhibits Wnt signaling [70]. In general, a more complex picture of Pcdh gene expression is emerging, in which distinct Pcdh gene clusters are expressed in different types of neurons, and the alternate and C-type isoforms are differentially expressed during the development of neural circuits [4, 16, 60]. …”

Section: Discussionmentioning

confidence: 99%

Structural origins of clustered protocadherin-mediated neuronal barcoding

Rubinstein¹,

Goodman²,

Maniatis³

et al. 2017

Seminars in Cell & Developmental Biology

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Clustered protocadherins mediate neuronal self-recognition and non-self discrimination—neuronal “barcoding”—which underpin neuronal self-avoidance in vertebrate neurons. Recent structural, biophysical, computational, and cell-based studies on protocadherin structure and function have led to a compelling molecular model for the barcoding mechanism. Protocadherin isoforms assemble into promiscuous cis-dimeric recognition units and mediate cell-cell recognition through homophilic trans-interactions. Each recognition unit is composed of two arms extending from the membrane proximal EC6 domains. A cis-dimeric recognition unit with each arm coding adhesive trans homophilic specificity can generate a zipper-like assembly that in turn suggests a chain termination mechanism for self-vs-non-self-discrimination among vertebrate neurons.

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Section: Discussionmentioning

confidence: 99%

Structural origins of clustered protocadherin-mediated neuronal barcoding

Rubinstein¹,

Goodman²,

Maniatis³

et al. 2017

Seminars in Cell & Developmental Biology

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“…To determine if the Pcdh-cluster affected MGE/POA-derived cIN survival, constitutive Pcdh-cluster knockout mice were crossed to Nkx2-1 Cre ;Ai14 mice (Figure 7a). Similarly to the deletion of Pcdh-cluster, mice carrying a deletion of the entire Pcdhcluster, are viable, fertile and of a normal weight (Figure C, top graph) (Chen et al 2017) The density of cIN was similar between mice lacking -Pcdhs and controls ( Figure 7C). The above results indicate that unlike the Pcdh-γ cluster that is essential for the regulation of cIN elimination, the function of -or -Pcdhs is dispensable for the survival of MGE/POA-derived cINs.…”

Section: Alpha and Beta Pcdhs Do Not Impact Cin Survivalmentioning

confidence: 85%

Clustered γ-Protocadherins Regulate Cortical Interneuron Programmed Cell Death

Mancia¹,

Spatazza²,

Rakela³

et al. 2020

Preprint

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Cortical function critically depends on inhibitory/excitatory balance. Cortical inhibitory interneurons (cINs) are born in the ventral forebrain. After completing their migration into cortex, their final numbers are adjustedduring a period of postnatal development -by programmed cell death. The mechanisms that regulate cIN elimination remains controversial. Here we show that genes in the protocadherin (Pcdh)-γ gene cluster, but not in the Pcdh-α or Pcdh-β clusters, are required for the survival of cINs through a BAX-dependent mechanism. Surprisingly, the physiological and morphological properties of Pcdh-γ deficient and wild type cINs during cIN cell death were indistinguishable. Co-transplantation of wild type and Pcdh-γ deficient interneuron precursor cells demonstrate that: 1) the number of mutant cINs eliminated was much higher than that of wild type cells, but the proportion of mutant or WT cells undergoing cell death was not affected by their density; 2) the presence of mutant cINs increases cell death among wild-type counterparts, and 3) cIN survival is dependent on the expression of Pcdh-γ C3, C4, and C5. We conclude that Pcdh-γ, and specifically γC3, γC4, and γC5, play a critical role in regulating cIN survival during the endogenous period of programmed cIN death. SignificanceInhibitory cortical interneurons (cIN) in the cerebral cortex originate from the ventral embryonic forebrain. After a long migration, they come together with local excitatory neurons to form cortical circuits. These circuits are responsible for higher brain functions, and the improper balance of excitation/inhibition in the cortex can result in mental diseases. Therefore, an understanding of how the final number of cINs is determined is both biologically and, likely, therapeutically significant. Here we show that cell surface homophilic binding proteins belonging to the clustered protocadherin gene family, specifically three isoforms in the Pcdh-γ cluster, play a key role in the regulation cIN programmed cell death. Co-transplantation of mutant and wild-type cINs shows that Pcdh-γ genes have cell-autonomous and non-cell autonomous roles in the regulation of cIN cell death. This work will help identify the molecular mechanisms and cell-cell interactions that determine how the proper ratio of excitatory to inhibitory neurons is determined in the cerebral cortex.

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“…Our model assumes no self-avoidance or biological feedback signals that depend on fiber density. Several factors have been reported to control the growth of distribution of serotonergic fibers, but this research has been heavily influenced by the notion that orderly distribution cannot be achieved without tight biological control (see, for example, Chen et al (2017)). The simulation results provide evidence that a considerable degree of self-organization can be achieved with simple assumptions, but it does not rule out these factors.…”

Section: Discussionmentioning

confidence: 99%

Serotonergic Axons as Fractional Brownian Motion Paths: Insights into the Self-organization of Regional Densities

Janušonis

Detering

Metzler

et al. 2019

Preprint

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All vertebrate brains contain a dense matrix of thin fibers that release serotonin (5hydroxytryptamine), a neurotransmitter that modulates a wide range of neural, glial, and vascular processes. Perturbations in the density of this matrix have been associated with a number of mental disorders, including autism and depression, but its self-organization and plasticity remain poorly understood. We introduce a model based on reflected Fractional Brownian Motion (FBM), a rigorously defined stochastic process, and show that it recapitulates some key features of regional serotonergic fiber densities. Specifically, we use supercomputing simulations to model fibers as FBM-paths in two-dimensional brain-like domains and demonstrate that the resultant steady state distributions approximate the fiber distributions in physical brain sections immunostained for the serotonin transporter (a marker for serotonergic axons in the adult brain). We suggest that this framework can support predictive descriptions and manipulations of the serotonergic matrix and that it can be further extended to incorporate the detailed physical properties of the fibers and their environment.

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Pcdhαc2 is required for axonal tiling and assembly of serotonergic circuitries in mice

Cited by 137 publications

References 48 publications

Structural origins of clustered protocadherin-mediated neuronal barcoding

Structural origins of clustered protocadherin-mediated neuronal barcoding

Clustered γ-Protocadherins Regulate Cortical Interneuron Programmed Cell Death

Serotonergic Axons as Fractional Brownian Motion Paths: Insights into the Self-organization of Regional Densities

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