Etv1 Controls the Establishment of Non-overlapping Motor Innervation of Neighboring Facial Muscles during Development

Tenney, Alan P.; Livet, Jean; Belton, Timothy; Procházková, Michaela; Pearson, Erica M.; Whitman, Mary C.; Kulkarni, Ashok B.; Engle, Elizabeth C.; Henderson, Christopher E.

doi:10.1016/j.celrep.2019.08.078

Cited by 15 publications

(13 citation statements)

References 71 publications

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“…LOCs and MOCs arise from a common progenitor pool with and develop alongside FMNs, raising the question of how OCNs deviate from a typical motor neuron fate to play such an unorthodox role in peripheral sensory modulation 9,10 . To learn more about the transcriptional origins of their unique developmental and mature properties, we compared all OCNs to a cluster of FMNs, which was identified based on co-expression of Etv1 and Epha7 ( Figure S2A, B ) 46 . Our analysis revealed substantial transcriptional differences between OCNs and FMNs that could contribute to their distinct functions and anatomy ( Figure S2C ).…”

Section: Resultsmentioning

confidence: 99%

Experience-dependent flexibility in a molecularly diverse central-to-peripheral auditory feedback system

Frank

Sitko

Suthakar

et al. 2022

Preprint

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Brainstem olivocochlear neurons (OCNs) modulate the earliest stages of auditory processing through feedback projections to the cochlea and have been shown to influence hearing and protect the ear from sound-induced damage through unclear mechanisms. Here, we used single-nucleus sequencing, anatomical reconstructions, and electrophysiology to characterize OCNs during postnatal development and after sound exposure. We identified markers for known OCN subtypes, medial (MOC) and lateral (LOC) OCNs, and show that they express distinct cohorts of physiologically relevant genes that change over development. In addition, we discovered a neuropeptide-enriched LOC subtype that produces Neuropeptide Y along with other neurotransmitters. Throughout the cochlea, both LOC subtypes extend arborizations over wide frequency domains. Moreover, LOC neuropeptide expression is strongly upregulated days after acoustic trauma, potentially providing a sustained protective signal to the cochlea. OCNs are therefore poised to have diffuse, dynamic effects on early auditory processing over timescales ranging from milliseconds to days.

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Section: Resultsmentioning

confidence: 99%

Experience-dependent flexibility in a molecularly diverse central-to-peripheral auditory feedback system

Frank

Sitko

Suthakar

et al. 2022

Preprint

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“…This study identified a previously unknown role of Etv1 in SC differentiation and myelination. In contrast with other ETS domain TF superfamily members, Etv1 has been implicated in controlling the formation of functional connections between sensory afferents and motor neurons (17), the terminal maturation program of cerebellar granule cells (18), and the establishment of motor innervation of adjacent muscles (21). Based on the data analysis of gene expression profiles of myelinating SCs (Figure 1 and Table S1) and the in vitro and in vivo experiments, our study demonstrated that Etv1 depletion in SCs dramatically impairs SC proliferation, migration, and differentiation, and abrogates SC re-myelination in the regenerated sciatic nerves.…”

Section: Discussionmentioning

confidence: 99%

“…Etv1/Er81 as a member of the ETS family that is involved in the regulation of neuronal specialization, muscle spindle differentiation, and sensorimotor connectivity (17)(18)(19). The role of Etv1 has been studied primarily in a subpopulation of spinal motor neurons, and researchers have shown that the intrinsic expression pattern and cell body localization of Etv1 coordinates motor neuron process terminal arborization (20,21). Fleming and colleagues reported that Etv1 is required in a subset of the receptor tyrosine kinase positive (RET + ) mechanosensory neurons to form the functional pacinian corpuscles, which consists of a single myelinated axon and multiple layers of non-myelinating SCs (22).…”

Section: Introductionmentioning

confidence: 99%

The Etv1/Er81 transcription factor coordinates myelination-related genes to regulate Schwann cell differentiation and myelination

Askar¹,

Xu²,

Hu³

et al. 2022

Ann Transl Med

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Background: Axonal myelination is critical for the functioning of vertebrate nervous system. Myelin sheath malformation or degeneration can cause a variety of neurological diseases. Our previous study identified multiple potential myelination-related transcriptional factors (TFs), including expressed sequence tag (ETS) variant transcription factor 1 (Etv1)/Er81, via gene microarray analysis of Schwann cells (SCs) at various myelination stages. Etv1 is known to be involved in the regulation of neuronal specialization, muscle spindle differentiation, and sensorimotor connectivity. However, to our knowledge, to date, there are no relevant studies that Etv1 regulates SC myelination. Methods: To investigate the roles of Etv1 in SC re-myelination, an in vivo mouse myelination model was used, in which the sciatic nerve is crushed. Etv1 in nerves was knocked down via in situ injection of cholesterol-modified Etv1-small interfering (si)RNA. The expression of myelin-associated glycoprotein (MAG) was evaluated by Western blotting (WB) and immunohistochemistry (IHC). Myelination was assessed by transmission electron microscopy (TEM). The effects of Etv1 on SC proliferation, migration, and differentiation were assessed in vitro using the EdU cell proliferation kit, a culture-insert scratch assay, a SC aggregate sphere migration assay on the axons of dorsal root ganglions (DRGs), and a SC differentiation model. Chromatin immunoprecipitation (ChIP) united with quantitative real-time PCR (qPCR), known as ChIP-qPCR, and luciferase activity reporter assays were performed to explore the possible mechanisms by which Etv1 controls SC differentiation and myelination. Results: The results demonstrated that Etv1 promoted myelination by facilitating SC proliferation, migration, and differentiation. Etv1 expression in SCs was upregulated during re-myelination, and knocking down Etv1 expression dramatically abrogated SC re-myelination in the crushed sciatic nerves. Moreover, silencing of Etv1 by siRNA in SCs in vitro inhibited its migration, proliferation, and differentiation. The results of ChIP-qPCR and luciferase reporter assay showed that Etv1 may regulate SC differentiation and myelination by binding to the promoters of myelination-related genes, such as MAG and Runx2, to initiate their transcription. Conclusions: Taken together, these findings demonstrated a previously unknown role of Etv1 in SC differentiation and myelination, providing a candidate molecular target for clinical interventions in demyelinating diseases.

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“…Remarkably, murine orthologue of up-regulated in kalirin–GEF1–inhibited cells ETV1 is expressed in the nuclei of mouse cranial nerves ( Zeisel et al, 2018 ). More precisely, Etv1 expression appears in facial motor neurons during the final post-tangential stage of their migration, the sub-nuclear segregation, and is indispensable for finalising neuronal differentiation ( Zhu & Guthrie, 2013 ; Tenney et al, 2019 ). Kalirin–GEF1 inhibition up-regulates low-risk specific transcriptomic traits in ADRN NB, which can be interpreted as a sign of a differentiation-like process.…”

Section: Discussionmentioning

confidence: 99%

Kalirin-RAC controls nucleokinetic migration in ADRN-type neuroblastoma

et al. 2021

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The migrational propensity of neuroblastoma is affected by cell identity, but the mechanisms behind the divergence remain unknown. Using RNAi and time-lapse imaging, we show that ADRN-type NB cells exhibit RAC1- and kalirin-dependent nucleokinetic (NUC) migration that relies on several integral components of neuronal migration. Inhibition of NUC migration by RAC1 and kalirin-GEF1 inhibitors occurs without hampering cell proliferation and ADRN identity. Using three clinically relevant expression dichotomies, we reveal that most of up-regulated mRNAs in RAC1- and kalirin–GEF1–suppressed ADRN-type NB cells are associated with low-risk characteristics. The computational analysis shows that, in a context of overall gene set poverty, the upregulomes in RAC1- and kalirin–GEF1–suppressed ADRN-type cells are a batch of AU-rich element–containing mRNAs, which suggests a link between NUC migration and mRNA stability. Gene set enrichment analysis–based search for vulnerabilities reveals prospective weak points in RAC1- and kalirin–GEF1–suppressed ADRN-type NB cells, including activities of H3K27- and DNA methyltransferases. Altogether, these data support the introduction of NUC inhibitors into cancer treatment research.

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Etv1 Controls the Establishment of Non-overlapping Motor Innervation of Neighboring Facial Muscles during Development

Abstract: Highlights d Developing somatotopic facial motor neurons are transcriptionally diverse d Etv1 is required for dorsolateral facial-motor neuron migration and axon targeting d Axon mistargeting makes the eyelid muscle ''whisk'' in Etv1 mutants

Cited by 15 publications

References 71 publications

Experience-dependent flexibility in a molecularly diverse central-to-peripheral auditory feedback system

Experience-dependent flexibility in a molecularly diverse central-to-peripheral auditory feedback system

The Etv1/Er81 transcription factor coordinates myelination-related genes to regulate Schwann cell differentiation and myelination

Kalirin-RAC controls nucleokinetic migration in ADRN-type neuroblastoma

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