Alpha protocadherins and Pyk2 kinase regulate cortical neuron migration and cytoskeletal dynamics via Rac1 GTPase and WAVE complex in mice

Fan, Li; Lu, Yichao; Shen, Xiulian; Shao, Haibao; Suo, Lun; Wu, Qiang

doi:10.7554/elife.35242

Cited by 54 publications

(71 citation statements)

References 63 publications

(141 reference statements)

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“…Perhaps not surprisingly, these mutant mice display defects in visual discrimination behaviors that assess visual acuity (Meguro et al 2015). Pcdhα genes have also been implicated in dendritic development and spine morphogenesis (Suo et al 2012), and more recently in cortical neuron migration (Fan et al 2018). Together, these findings support additional roles for Pcdh isoforms that are likely independent of self-avoidance.…”

Section: Supplemental Text Sectionmentioning

confidence: 77%

Writing, Reading, and Translating the Clustered Protocadherin Cell Surface Recognition Code for Neural Circuit Assembly

Mountoufaris

Canzio

Nwakeze

et al. 2018

Annu. Rev. Cell Dev. Biol.

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The ability of neurites of individual neurons to distinguish between themselves and neurites from other neurons and to avoid self (self-avoidance) plays a key role in neural circuit assembly in both invertebrates and vertebrates. Similarly, when individual neurons of the same type project into receptive fields of the brain, they must avoid each other to maximize target coverage (tiling). Counterintuitively, these processes are driven by highly specific homophilic interactions between cell surface proteins that lead to neurite repulsion rather than adhesion. Among these proteins in vertebrates are the clustered protocadherins (Pcdhs), and key to their function is the generation of enormous cell surface structural diversity. Here we review recent advances in understanding how a Pcdh cell surface code is generated by stochastic promoter choice; how this code is amplified and read by homophilic interactions between Pcdh complexes at the surface of neurons; and, finally, how the Pcdh code is translated to cellular function, which mediates self-avoidance and tiling and thus plays a central role in the development of complex neural circuits. Not surprisingly, Pcdh mutations that diminish homophilic interactions lead to wiring defects and abnormal behavior in mice, and sequence variants in the Pcdh gene cluster are associated with autism spectrum disorders in family-based genetic studies in humans.

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Section: Supplemental Text Sectionmentioning

confidence: 77%

Writing, Reading, and Translating the Clustered Protocadherin Cell Surface Recognition Code for Neural Circuit Assembly

Mountoufaris

Canzio

Nwakeze

et al. 2018

Annu. Rev. Cell Dev. Biol.

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“…12,13 In contrast, Pyk2 is enriched in the postsynaptic density of neurons and serves to tune synaptic plasticity and regulate neuronal differentiation and migration in the CNS. [14][15][16][17][18][19][20] Pyk2 signaling is also involved in bone remodeling and leukocyte motility. 3,21 Canonical FAK activation involves recruitment to membrane focal adhesions via interactions with paxillin, talin, and vinculin at clustered integrins.…”

Section: Introductionmentioning

confidence: 99%

Conformational dynamics of FERM-mediated autoinhibition in Pyk2 tyrosine kinase

Loving

Underbakke

2019

Preprint

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Pyk2 is a non-receptor tyrosine kinase that evolved from gene duplication of focal adhesion kinase (FAK) and subsequent functional specialization in the brain and hemopoietic cells. Pyk2 shares a domain organization with FAK, with an N-terminal regulatory FERM domain adjoining the kinase domain. FAK regulation involves integrin-mediated membrane clustering to relieve autoinhibitory interactions between FERM and kinase domains. Pyk2 regulation remains cryptic, involving Ca 2+ influx and protein scaffolding. While the mechanism of the FAK FERM domain in autoinhibition is well-established, the regulatory role of the Pyk2 FERM is ambiguous. We probed the mechanisms of FERM-mediated autoinhibition of Pyk2 using hydrogen/deuterium exchange mass spectrometry (HDX-MS) and kinase activity profiling. The results reveal FERM-kinase interfaces responsible for autoinhibition. Pyk2 autoinhibition impacts activation loop conformation. In addition, the autoinhibitory FERM-kinase interface exhibits allosteric linkage with the FERM basic patch conserved in both FAK and Pyk2.

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“…Similar to the enormous diversity of DSCAM1 proteins in Drosophila, combinatorial cisand trans-interactions between mammalian clustered cell-surface protocadherin (Pcdh) proteins, encoded by the three closely-linked gene clusters (, , and ), endow individual neurons with a unique identity code and specific self-recognition module, which are required for neuronal migration, dendrite self-avoidance, and axon tiling in the brain [25][26][27][28][29][30][31]. The human Pcdh cluster contains 13 highly-similar, tandem-arrayed, unusually-large "alternate" variable exons (1-13) and 2 divergent "ubiquitous" variable exons (c1-c2), followed by 3 downstream small constant exons ( Figure 1A), reminiscent of the variable and constant genome organizations of immunoglobulin (Ig) and T-cell receptor (Tcr) clusters [25,32].…”

Section: Exogenous Ctcf Sites As Protocadherin Insulatorsmentioning

confidence: 99%

Tandem Directional CTCF Sites Balance Protocadherin Promoter Usage

Guo

et al. 2019

Preprint

Self Cite

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CTCF is a key insulator-binding protein and mammalian genomes contain numerous CTCFbinding sites (CBSs), many of which are organized in tandem arrays. Here we provide direct evidence that CBSs, if located between enhancers and promoters in the Pcdh and -globin clusters, function as an enhancer-blocking insulator by forming distinct directional chromatin loops, regardless whether enhancers contain CBS or not. Moreover, computational simulation and experimental capture revealed balanced promoter usage in cell populations and stochastic monoallelic expression in single cells by large arrays of tandem variable CBSs. Finally, gene expression levels are negatively correlated with CBS insulators located between enhancers and promoters on a genome-wide scale. Thus, single CBS insulators ensure proper enhancer insulation and promoter activation while tandem-arrayed CBS insulators determine balanced promoter usage. This finding has interesting implications on the role of topological insulators in 3D genome folding and developmental gene regulation.2 22]. Insertion, mutation, deletion, inversion, or duplication of CBS elements alters chromatin topology and gene expression [12, 14-16, 18, 22-24]. Emerging evidence suggests that spatial control of genome topology by CTCF/Cohesin regulates gene expression; however, how numerous CBS elements in mammalian genomes function as insulators to control proper promoter activation and balanced usage remains obscure. RESULTS Exogenous CTCF Sites as Protocadherin InsulatorsSimilar to the enormous diversity of DSCAM1 proteins in Drosophila, combinatorial cisand trans-interactions between mammalian clustered cell-surface protocadherin (Pcdh) proteins, encoded by the three closely-linked gene clusters (, , and ), endow individual neurons with a unique identity code and specific self-recognition module, which are required for neuronal migration, dendrite self-avoidance, and axon tiling in the brain [25][26][27][28][29][30][31]. The human Pcdh cluster contains 13 highly-similar, tandem-arrayed, unusually-large "alternate" variable exons (1-13) and 2 divergent "ubiquitous" variable exons (c1-c2), followed by 3 downstream small constant exons ( Figure 1A), reminiscent of the variable and constant genome organizations of immunoglobulin (Ig) and T-cell receptor (Tcr) clusters [25,32]. Each of the 13 "alternate" variable exons (1-13) carries its own promoter, which is flanked by two forward-oriented CBS (CSE and eCBS) elements ( Figure 1A). However, the c1 "ubiquitous" promoter carries only one forward-oriented CBS and the c2 promoter has no CBS element ( Figure 1A). Two distal Pcdh enhancers, HS7 and HS5-1, are located downstream, and one of which, HS5-1, is flanked by two reverse-oriented CBS (HS5-1a and HS5-1b) elements [33,34]. Multiple longdistance chromatin interactions between these enhancers and Pcdh target promoters form a transcription hub and determine the promoter choice [34,35]. We performed single-cell RNAseq of mouse cortical neurons and found members of the Pcdh clu...

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Alpha protocadherins and Pyk2 kinase regulate cortical neuron migration and cytoskeletal dynamics via Rac1 GTPase and WAVE complex in mice

Cited by 54 publications

References 63 publications

Writing, Reading, and Translating the Clustered Protocadherin Cell Surface Recognition Code for Neural Circuit Assembly

Writing, Reading, and Translating the Clustered Protocadherin Cell Surface Recognition Code for Neural Circuit Assembly

Conformational dynamics of FERM-mediated autoinhibition in Pyk2 tyrosine kinase

Tandem Directional CTCF Sites Balance Protocadherin Promoter Usage

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