γ-Protocadherins Control Cortical Dendrite Arborization by Regulating the Activity of a FAK/PKC/MARCKS Signaling Pathway

Garrett, Andrew M.; Schreiner, Dietmar; Lobas, Mark A.; Weiner, Joshua A.

doi:10.1016/j.neuron.2012.01.028

Cited by 170 publications

(342 citation statements)

References 56 publications

(81 reference statements)

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“…This diversity appears to play a fundamental role in neural circuit assembly (22)(23)(24)(25). Understanding the mechanism by which this diversity is generated is, therefore, fundamental to understanding the development and function of the nervous system.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have revealed a functional role for clustered Pcdh genes in dendritic development and self-avoidance [22][23][24][25]. Strikingly, a repertoire of heterozygous mutations in chromatid-segregating cohesin (SMC1A, SMC3, RAD21) and cohesin regulators (NIPBL, ESCO2) have been found to cause a class of developmental disorders known as Cornelia de Lange syndrome (CdLS) and Robert syndrome in humans (31).…”

Section: Discussionmentioning

confidence: 99%

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CTCF/cohesin-mediated DNA looping is required for protocadherin α promoter choice

Guo

Monahan

et al. 2012

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

242

329

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The closely linked human protocadherin (Pcdh) α, β, and γ gene clusters encode 53 distinct protein isoforms, which are expressed in a combinatorial manner to generate enormous diversity on the surface of individual neurons. This diversity is a consequence of stochastic promoter choice and alternative pre-mRNA processing. Here, we show that Pcdhα promoter choice is achieved by DNA looping between two downstream transcriptional enhancers and individual promoters driving the expression of alternate Pcdhα isoforms. In addition, we show that this DNA looping requires specific binding of the CTCF/cohesin complex to two symmetrically aligned binding sites in both the transcriptionally active promoters and in one of the enhancers. These findings have important implications regarding enhancer/promoter interactions in the generation of complex Pcdh cell surface codes for the establishment of neuronal identity and self-avoidance in individual neurons.T he clustered protocadherin (Pcdh) genes are expressed in the nervous system and organized into three closely linked clusters (α, β, and γ) (1-5). The human Pcdhα gene cluster contains 13 highly similar variable first exons (α1 to α13) arrayed in tandem and two more distantly related c-type variable first exons designated αc1 and αc2 (Fig. 1A). The variable first exons encode the extracellular, transmembrane, and juxtamembrane intracellular domains of the Pcdhα proteins. Each of these 15 variable first exons is cis-spliced to a single set of three downstream constant exons that encode a distal intracellular domain (1-3). The human β cluster is located downstream from the α cluster and contains a tandem array of 16 highly similar variable exons but with no constant exons, whereas the γ cluster contains 22 variable first exons arrayed in tandem and divided into three types (γa1 to γa12, γb1 to γb7, and γc3 to γc5) (Fig. 1D). As in the case of the α cluster, each of these 22 γ variable first exons is cis-spliced to a single set of three downstream constant exons, which are distinct from the α constant exons, to generate diverse γ mRNAs (1, 3, 6). Analyses of the α and γ transcripts have revealed that highly similar Pcdh alternate isoforms are expressed in a stochastic fashion, whereas all of the c-type divergent isoforms, αc1 and αc2 in the α cluster and γc3, γc4, and γc5 in the γ cluster, are expressed ubiquitously in all cells (1-3, 5, 7). Hereafter, we refer to the c-type genes as "ubiquitously expressed" in contrast to the "alternately expressed" Pcdh genes ( Fig. 1 A and D). A combination of stochastic activation of alternate promoters and constitutive activation of c-type ubiquitous promoters generates enormous single-cell diversity on the surface of individual neurons.Significant advances have been made in understanding the mechanisms by which individual neurons express distinct combinations of the clustered Pcdh genes (2, 3, 8-10). Two long-range cis-regulatory elements in the α cluster, HS5-1 and HS7 (hypersensitive sites 5-1 and 7), function as developmental and tissue...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

CTCF/cohesin-mediated DNA looping is required for protocadherin α promoter choice

Guo

Monahan

et al. 2012

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

242

329

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“…That study, however, suggested that Pcdhc and Slit-Robo signals independently mediate dendritic self-avoidance, leaving their functional relationships to be determined in the future. In the cerebral cortex, loss of Pcdhc genes reduces arborization of the apical dendrites of neurons (Garrett et al, 2012). Furthermore, knockout of the Pcdha cluster also impairs dendrite arbor formation in hippocampal neurons (Suo et al, 2012).…”

Section: Regulation Of Neurite Patterning By Clustered Protocadherinsmentioning

confidence: 99%

Emerging roles of protocadherins: from self-avoidance to enhancement of motility

Hayashi

Takeichi

2015

Journal of Cell Science

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Protocadherins are a group of transmembrane proteins belonging to the cadherin superfamily that are subgrouped into 'clustered' and 'nonclustered' protocadherins. Although cadherin superfamily members are known to regulate various forms of cell-cell interactions, including cell-cell adhesion, the functions of protocadherins have long been elusive. Recent studies are, however, uncovering their unique roles. The clustered protocadherins regulate neuronal survival, as well as dendrite self-avoidance. Combinatorial expression of clustered protocadherin isoforms creates a great diversity of adhesive specificity for cells, and this process is likely to underlie the dendritic selfavoidance. Non-clustered protocadherins promote cell motility rather than the stabilization of cell adhesion, unlike the classic cadherins, and mediate dynamic cellular processes, such as growth cone migration. Protocadherin dysfunction in humans is implicated in neurological disorders, such as epilepsy and mental retardation. This Commentary provides an overview of recent findings regarding protocadherin functions, as well as a discussion of the molecular basis underlying these functions.

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“…We recently found that the ␥-Pcdhs promote dendritic arborization in cortical neurons by inhibiting a signaling pathway involving FAK, PKC, and the PKC target myristoylated alanine-rich protein kinase C substrate (MARCKS) (9). The C-terminal ␥-Pcdh constant domain binds to FAK and prevents its autophosphorylation (29).…”

mentioning

confidence: 99%

Protein Kinase C Phosphorylation of a γ-Protocadherin C-terminal Lipid Binding Domain Regulates Focal Adhesion Kinase Inhibition and Dendrite Arborization

Keeler

Schreiner

Weiner

2015

Journal of Biological Chemistry

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Background: ␥-Protocadherin adhesion molecules regulate dendrite arborization by inhibiting focal adhesion kinase (FAK). Results: Protein kinase C (PKC) phosphorylation of a C-terminal serine disrupts ␥-protocadherin inhibition of FAK and reduces dendrite arborization. Conclusion:The ability of the ␥-protocadherins to promote dendrite arborization is regulated by phosphorylation. Significance: These data provide much-needed mechanistic insight into the regulation of a critical neurodevelopmental adhesion molecule.

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γ-Protocadherins Control Cortical Dendrite Arborization by Regulating the Activity of a FAK/PKC/MARCKS Signaling Pathway

Cited by 170 publications

References 56 publications

CTCF/cohesin-mediated DNA looping is required for protocadherin α promoter choice

CTCF/cohesin-mediated DNA looping is required for protocadherin α promoter choice

Emerging roles of protocadherins: from self-avoidance to enhancement of motility

Protein Kinase C Phosphorylation of a γ-Protocadherin C-terminal Lipid Binding Domain Regulates Focal Adhesion Kinase Inhibition and Dendrite Arborization

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