The Transcription Factor Ets1 Influences Axonal Growth via Regulation of Lcn2

Gu, Miao; Li, Xiaodi; Wu, Ronghua; Cheng, Xiao; Zhou, Songlin; Gu, Xiaosong

doi:10.1007/s12035-023-03616-0

Cited by 2 publications

(2 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2F ) 34 . Remarkably, BDNF genes are enriched for transcription factors reported to trigger neuron-intrinsic regeneration pathways in response to axonal injury 3,10,35 We found known BDNF-responsive genes are significantly enriched for the transcription factors STAT3 36 , TP53 37,38 , CREB 39 , ELK1 40 , SP1 14 , SRF 41 , ETS1 42 , and Jun 43,44 ( Fig. 2F ).…”

Section: Resultsmentioning

confidence: 91%

BDNF controls phosphorylation and transcriptional networks governing cytoskeleton organization and axonal regeneration

Vargas,

Brown,

Sun

et al. 2023

Preprint

View full text Add to dashboard Cite

SUMMARYAxonal degeneration underlies neuromuscular disorders and neuropathies. Dysregulation of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), in the peripheral nervous system has long been established to exacerbate axonopathy. However, the molecular programs controlled by BDNF that facilitate axonal regeneration and transport are not well-understood. Here, we unravel the transcriptomic and phosphorylation landscape shaped by BDNF in human iPSC-derived motor neurons. Using SLAM-Seq, we reveal BDNF stimulation increases global transcription rate in motor neurons and governs gene regulatory networks that converge with those engaged during axonal repair/outgrowth. Phosphoproteomic analyses demonstrate that BDNF remodels the phosphorylation landscape of cytoskeletal-binding proteins, especially of structural microtubule-associated proteins. Importantly, the localized axonal-specific activation of ERK1/2 is necessary for BDNF to enhance axonal transport of neurotrophin-containing signaling endosomes and to potentiate axonal regeneration after axotomy. Collectively, this work unveils a novel molecular paradigm that positions BDNF as a core regulator of transcriptional and phosphorylation programs driving axonal regeneration and transport in human motor neurons.HIGHLIGHTSSLAM-seq reveals increased global transcriptional rate by BDNF in human motor neuronsBDNF modulates transcriptional programs that potentiate axonal outgrowth/regenerationBDNF governs the phosphorylation landscape of cytoskeletal-binding proteinsAxonal BDNF-ERK1/2 signaling controls axonal transport and axonal regeneration

show abstract

Section: Resultsmentioning

confidence: 91%

BDNF controls phosphorylation and transcriptional networks governing cytoskeleton organization and axonal regeneration

Vargas,

Brown,

Sun

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…The upregulation of Syt7 in only spinal motor neurons is indicative of their need to reorganize presynaptic function, while the upregulation of Lcn2 on the other hand appears to be a way to negatively control regeneration (Gu et al 2024), perhaps a way to block motor neurons that are already handling too much stress- and DNA damage responses from regenerating, but this remains to be further investigated. Hypoglossal motor neurons also showed an induction of regenerative genes including Gap43 , Cd44 and Chl1 .…”

Section: Discussionmentioning

confidence: 99%

Transcriptional modulation unique to vulnerable motor neurons predicts ALS across species and SOD1 mutations

Mei,

Nichterwitz,

Leboeuf

et al. 2024

Preprint

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of somatic motor neurons (MNs), which innervate skeletal muscles. However, certain MN groups including ocular MNs that regulate eye movement are relatively resilient to ALS. To reveal mechanisms of differential MN vulnerability, we investigate the transcriptional dynamics of two vulnerable and two resilient MN populations in SOD1G93A ALS mice. Differential gene expression analysis shows that each neuron type displays a largely unique spatial and temporal response to ALS. Resilient MNs regulate few genes in response to disease, but show clear divergence in baseline gene expression compared to vulnerable MNs, which in combination may hold the key to their resilience. EASE, fGSEA and ANUBIX enrichment analysis demonstrate that vulnerable MN groups share pathway activation, including regulation of neuronal death, inflammatory response, ERK and MAPK cascades, cell adhesion and synaptic signaling. These pathways are largely driven by 11 upregulated genes, including Atf3, Cd44, Gadd45a, Ngfr, Ccl2, Ccl7, Gal, Timp1, Nupr1, Serpinb1a and Chl1, and indicate that cell death occurs through similar mechanisms across vulnerable MNs albeit with distinct timing. Machine learning using DEGs upregulated in our SOD1G93A spinal MNs predict disease in human stem cell-derived MNs harboring the SOD1E100G mutation, and show that dysregulation of VGF, PENK, INA and NTS are strong disease-predictors across SOD1 mutations and species. Meta-analysis across mouse SOD1 transcriptome datasets identified a shared transcriptional vulnerability code of 32 genes including e.g Sprr1a, Atf3, Fgf21, C1qb, Nupr1, Gap43, Adcyap1, Vgf, Ina and Mt1. In conclusion our study reveals vulnerability-specific gene regulation that may act to preserve neurons and can be used to predict disease.

show abstract

The Transcription Factor Ets1 Influences Axonal Growth via Regulation of Lcn2

Cited by 2 publications

References 40 publications

BDNF controls phosphorylation and transcriptional networks governing cytoskeleton organization and axonal regeneration

BDNF controls phosphorylation and transcriptional networks governing cytoskeleton organization and axonal regeneration

Transcriptional modulation unique to vulnerable motor neurons predicts ALS across species and SOD1 mutations

Contact Info

Product

Resources

About