Elongator controls cortical interneuron migration by regulating actomyosin dynamics

Tielens, Sylvia; Huysseune, Sandra; Godin, Juliette D.; Chariot, Alain; Malgrange, Brigitte; Nguyen, Laurent

doi:10.1038/cr.2016.112

Cited by 34 publications

(29 citation statements)

References 63 publications

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“…Immature interneurons have to quickly adapt their morphology in regard to changing external guidance cues during their migration from their sites of origin in the basal telencephalon towards cortical targets [114][115][116][117]. Therefore, the expression of genes important for the composition and arrangement of cytoskeletal compartments as well as membrane-bound proteins like specific guidance receptors has to be rapidly adapted upon signal detection and integration [116,[118][119][120][121][122]. Often, these processes are regulated by protein phosphorylation [123][124][125][126], which also necessitates a flexible regulation of respective protein kinases like the PAKs [47,127,128].…”

Section: Discussionmentioning

confidence: 99%

DNMT1 modulates interneuron morphology by regulatingPak6expression through crosstalk with histone modifications

et al. 2018

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Epigenetic mechanisms of gene regulation, including DNA methylation and histone modifications, call increasing attention in the context of development and human health. Thereby, interactions between DNA methylating enzymes and histone modifications tremendously multiply the spectrum of potential regulatory functions. Epigenetic networks are critically involved in the establishment and functionality of neuronal circuits that are composed of gamma-aminobutyric acid (GABA)-positive inhibitory interneurons and excitatory principal neurons in the cerebral cortex. We recently reported a crucial role of the DNA methyltransferase 1 (DNMT1) during the migration of immature POA-derived cortical interneurons by promoting the migratory morphology through repression of Pak6. However, the DNMT1-dependent regulation of Pak6 expression appeared to occur independently of direct DNA methylation. Here, we show that in addition to its DNA methylating activity, DNMT1 can act on gene transcription by modulating permissive H3K4 and repressive H3K27 trimethylation in developing inhibitory interneurons, similar to what was found in other cell types. In particular, the transcriptional control of Pak6, interactions of DNMT1 with the Polycomb-repressor complex 2 (PCR2) core enzyme EZH2, mediating repressive H3K27 trimethylations at regulatory regions of the Pak6 gene locus. Similar to what was observed upon Dnmt1 depletion, inhibition of EZH2 caused elevated Pak6 expression levels accompanied by increased morphological complexity, which was rescued by siRNA-mediated downregulation of Pak6 expression. Together, our data emphasise the relevance of DNMT1-dependent crosstalk with histone tail methylation for transcriptional control of genes like Pak6 required for proper cortical interneuron migration.

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Section: Discussionmentioning

confidence: 99%

DNMT1 modulates interneuron morphology by regulatingPak6expression through crosstalk with histone modifications

et al. 2018

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“…There is accumulating evidence that IKAP/ELP1 and the Elongator complex participate in the organization of the cytoskeleton (36-39, 41, 48-52). Specifically, Elongator has been demonstrated to be required for normal neuronal branching (36,37,41,(48)(49)(50)(51), organization of actin networks (38), and acetylation of α-tubulin (40, 50, 52). Microtubules also have been shown to be altered in growth cones from peripheral neurons lacking IKAP/ELP1 in chick (36).…”

Section: Discussionmentioning

confidence: 99%

“…However, the failure to extend or maintain axons to mediate normal transport during target innervation could also ultimately cause neuronal death. In support of this thesis, IKAP/ELP1 has been shown to be necessary for normal cytoskeletal dynamics (36,38,39) and for the retrograde transport of NGF (40), whereas ELP3, the acetyl-transferase subunit of the Elongator complex, has been proposed to regulate actin dynamics (13,41). For a better understanding of why Ikbkap −/− neurons die, we investigated their behavior in vitro, examining their overall morphology, axon outgrowth, and growth cone dynamics.…”

Section: Bgp-15 Normalizes Impaired Actin Dynamics In Ikbkapmentioning

confidence: 99%

BGP-15 prevents the death of neurons in a mouse model of familial dysautonomia

Ohlen

Russell

Brownstein

et al. 2017

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

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Hereditary sensory and autonomic neuropathy type III, or familial dysautonomia [FD; Online Mendelian Inheritance in Man (OMIM) 223900], affects the development and long-term viability of neurons in the peripheral nervous system (PNS) and retina. FD is caused by a point mutation in the gene IKBKAP/ELP1 that results in a tissue-specific reduction of the IKAP/ELP1 protein, a subunit of the Elongator complex. Hallmarks of the disease include vasomotor and cardiovascular instability and diminished pain and temperature sensation caused by reductions in sensory and autonomic neurons. It has been suggested but not demonstrated that mitochondrial function may be abnormal in FD. We previously generated an Ikbkap/Elp1 conditional-knockout mouse model that recapitulates the selective death of sensory (dorsal root ganglia) and autonomic neurons observed in FD. We now show that in these mice neuronal mitochondria have abnormal membrane potentials, produce elevated levels of reactive oxygen species, are fragmented, and do not aggregate normally at axonal branch points. The small hydroxylamine compound BGP-15 improved mitochondrial function, protecting neurons from dying in vitro and in vivo, and promoted cardiac innervation in vivo. Given that impairment of mitochondrial function is a common pathological component of neurodegenerative diseases such as amyotrophic lateral sclerosis and Alzheimer's, Parkinson's, and Huntington's diseases, our findings identify a therapeutic approach that may have efficacy in multiple degenerative conditions.T he autonomic nervous system is essential for homeostasis, and its disruption in familial dysautonomia (FD) can have fatal consequences resulting from cardiovascular instability, respiratory dysfunction, and/or sudden death during sleep (1-3). In addition to developmental decreases in the number of sensory and autonomic neurons, FD patients undergo a progressive loss of peripheral neurons and retinal ganglion cells. The latter loss may ultimately lead to blindness (4, 5). More than 98% of FD cases result from a single base substitution (IVS20+6T > C) in the IKBKAP/ELP1 gene (3, 6). This mutation is carried by 1 in 27 to 1 in 32 Ashkenazi Jews (3, 6). The protein encoded by the IKBKAP/ELP1 gene, IKAP/ELP1, is a scaffolding protein for the six-subunit Elongator complex (ELP1-ELP6), which modifies tRNAs during translation (7). Why reduction in the IKAP/ ELP1 protein results in neuronal death is unknown, and we have sought to elucidate the cellular and molecular mechanisms that cause progressive neurodegeneration in FD to help identify treatments that improve neuronal function and viability.Accumulating evidence indicates that cells from FD patients and from mouse models with deletions in the Elongator subunits Ikbkap/Elp1 or Elp3 experience intracellular stress (4,5,(8)(9)(10) resulting from the direct and/or indirect consequences of impaired translation (7, 11). The C terminus of IKAP/ELP1 has been shown to bind c-Jun N-terminal kinase (JNK) and to regulate JNK cytosolic stress signaling (12)....

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“…The accumulation of actomyosin is controlled by an Elongator complex that is known to regulate the acetylation of tubulin in neurons and proper tRNA modifications in neural progenitors [ 71 , 72 ]. Conditional deletion of Elp3, an enzymatic core subunit of the Elongator complex, in cortical inhibitory interneurons increases the depolymerization of actin filaments and perturbs the accumulation of actomyosin at the nuclear rear or trailing process, resulting in reduction of the nuclear migration velocity [ 73 ]. Interestingly, deficiency of Elp3 suppresses the swelling formation in cortical inhibitory interneurons, suggesting its multiple roles in coordinated neuronal migration.…”

Section: Nuclear Deformation and Movementmentioning

confidence: 99%

Morphological and Molecular Basis of Cytoplasmic Dilation and Swelling in Cortical Migrating Neurons

2017

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During corticogenesis, neuronal migration is an essential step for formation of a functional brain, and abnormal migration is known to cause various neurological disorders. Neuronal migration is not just a simple movement of the cell body, but a consequence of various morphological changes and coordinated subcellular events. Recent advances in in vivo and ex vivo cell biological approaches, such as in utero gene transfer, slice culture and ex vivo chemical inhibitor techniques, have revealed details of the morphological and molecular aspects of neuronal migration. Migrating neurons have been found to have a unique structure, dilation or swelling, at the proximal region of the leading process; this structure is not found in other migrating cell types. The formation of this structure is followed by nuclear deformation and forward movement, and coordination of this three-step sequential morphological change (the dilation/swelling formation, nuclear elongation and nuclear movement) is essential for proper neuronal migration and the construction of a functional brain structure. In this review, we will introduce the morphological features of this unique structure in migrating neurons and summarize what is known about the molecules regulating the dilation/swelling formation and nuclear deformation and movement.

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Elongator controls cortical interneuron migration by regulating actomyosin dynamics

Cited by 34 publications

References 63 publications

DNMT1 modulates interneuron morphology by regulatingPak6expression through crosstalk with histone modifications

DNMT1 modulates interneuron morphology by regulatingPak6expression through crosstalk with histone modifications

BGP-15 prevents the death of neurons in a mouse model of familial dysautonomia

Morphological and Molecular Basis of Cytoplasmic Dilation and Swelling in Cortical Migrating Neurons

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