<scp>ENGRAILED</scp>‐1 transcription factor has a paracrine neurotrophic activity on adult spinal α‐motoneurons

Leboeuf, Mélanie; Abonce, Stephanie E. Vargas; Pezé-Hedsieck, Eugénie; Dupont, Edmond; Jimenez-Alonso, Lucia; Moya, Kenneth L.; Prochiantz, Alain

doi:10.15252/embr.202256525

Cited by 7 publications

(13 citation statements)

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“…As previously described (Leboeuf et al 2023), sections were washed in PBS, incubated with RNAscope hydrogen peroxide solution from Advanced Cell Diagnostics (ACD) for 10 min at room temperature (RT), rinsed in PBS 0.1% Tween 20 at RT, collected on Super Frost plus microscope slides (Thermo Scientific), dried at RT for 1 h, rapidly immersed in ultrapure water, dried again at RT for 1 h, heated for 1 h at 60°C, and dried at RT overnight. The next day, sections were immersed in ultrapure water, rapidly dehydrated with 100% ethanol, incubated at 100°C for 15 min in RNAscope 1X Target Retrieval Reagent (ACD), washed in ultrapure water, and dehydrated with 100% ethanol for 3 min at RT.…”

Section: Methodsmentioning

confidence: 99%

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

Mei,

Nichterwitz,

Leboeuf

et al. 2024

Preprint

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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.

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Section: Methodsmentioning

confidence: 99%

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

Mei,

Nichterwitz,

Leboeuf

et al. 2024

Preprint

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“…A second point is the specificity of cell targeting by HPs. In the case of EN1 and OTX2, the specific recognition of spinal αMNs and PV cells, respectively, is due to the interaction between glycosaminoglycans (GAGs) present at the cell surface and a GAG-binding motif overlapping with the HD first helix ( Beurdeley et al, 2012 ; Lebœuf et al, 2023 ). Although two HPs are not sufficient to validate a “sugar code” hypothesis for in vivo specific targeting, it is of note that GAG binding domains are present at a similar sequence position in many HPs ( Prochiantz and Di Nardo, 2015 ).…”

Section: Mechanisms Of Intercellular Transfer and Co-signalingmentioning

confidence: 99%

“…In the ventral spinal cord, V1 interneurons, including Renshaw cells, express EN1 while the En1 locus is not active in αMNs ( Wenner and O’Donovan, 1999 ; Sapir, 2004 ; Lebœuf et al, 2023 ). These large MNs receive synaptic input from V1 interneurons and capture secreted EN1 protein.…”

Section: Homeoprotein Therapeutic Activities In Animal Models Of Huma...mentioning

confidence: 99%

“…These large MNs receive synaptic input from V1 interneurons and capture secreted EN1 protein. When this transfer is blocked by the local expression of a secreted EN1-specific single-chain antibody (scFv-EN1), αMN retrograde degeneration is induced and muscular strength is partially lost ( Lebœuf et al, 2023 ). A similar degenerative phenotype is observed in the Swiss En1 -Het mouse ( Lebœuf et al, 2023 ).…”

Section: Homeoprotein Therapeutic Activities In Animal Models Of Huma...mentioning

confidence: 99%

“…Also related to growth cone behavior, VAX1 was shown to regulate RGC decussation at the level of the optic chiasma ( Kim et al, 2014 ; Min et al, 2023 ). In the adult, EN1 secreted by V1 interneurons in the mouse spinal cord is captured by motoneurons (MNs), and blocking this transfer induces αMN retrograde degeneration ( Lebœuf et al, 2023 ). In the juvenile and adult mouse, OTX2 signaling regulates the opening and closure of cerebral cortex critical periods (CPs) of plasticity in the visual, auditory, and medial prefrontal cortices ( Sugiyama et al, 2008 ).…”

Section: Introductionmentioning

confidence: 99%

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Therapeutic value of homeoprotein signaling pathways

Di Nardo,

Prochiantz

2024

Front. Neurosci.

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Cell signaling based on homeoprotein transfer is a pathway with developmental and physiological functions. For a few transcription factors of this family, primarily ENGRAILED1, ENGRAILED2 and OTX2, their physiological functions have led to therapeutic strategies in animal models of human diseases, including Parkinson’s disease, amyotrophic lateral sclerosis, amblyopia and anxiety-related disorders. In mesencephalic dopaminergic neurons which degenerate in Parkinson’s disease, ENGRAILED1/2 have cell autonomous activities, but their transducing properties enables their use as therapeutic proteins. In contrast, in spinal alpha-motoneurons, which are lost in amyotrophic lateral sclerosis, ENGRAILED1 is supplied by V1 interneurons. Thus, its use as a therapeutic protein to protect alpha-motoneurons against degeneration mimics its normal non-cell autonomous neurotrophic activity. OTX2, synthesized and secreted by the choroid plexus, is transferred to parvalbumin interneurons and exerts regulatory functions controlling cerebral cortex plasticity. Understanding the latter OTX2 function has led to strategies for manipulating visual acuity and anxiety-like behavior in adult mice. In this review, we describe these cases and what is known about the involved molecular mechanisms. Because the transduction sequences are conserved in most of the few hundred homeoproteins, we argue how this family of molecules constitutes an important reservoir of physiological knowledge, with potential consequences in the search for new therapeutic strategies.

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The limb dorsoventral axis: Lmx1b's role in development, pathology, evolution, and regeneration

Castilla‐Ibeas,

Zdral,

Oberg

et al. 2024

Developmental Dynamics

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The limb anatomy displays well‐defined dorsal and ventral compartments, housing extensor, and flexor muscles, which play a crucial role in facilitating limb locomotion and manipulation. Despite its importance, the study of limb dorsoventral patterning has been relatively neglected compared to the other two axes leaving many crucial questions about the genes and developmental processes implicated unanswered. This review offers a thorough overview of the current understanding of limb dorsoventral patterning, synthesizing classical literature with recent research. It covers the specification of dorsal fate in the limb mesoderm and its subsequent translation into dorsal morphologies—a process directed by the transcription factor Lmx1b. We also discuss the potential role of dorsoventral patterning in the evolution of paired appendages and delve into the involvement of LMX1B in Nail‐Patella syndrome, discussing the molecular and genetic aspects underlying this condition. Finally, the potential role of dorsoventral polarity in digit tip regeneration, a prominent instance of multi‐tissue regeneration in mammals is also considered. We anticipate that this review will renew interest in a process that is critical to limb function and evolutionary adaptations but has nonetheless been overlooked.

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ENGRAILED‐1 transcription factor has a paracrine neurotrophic activity on adult spinal α‐motoneurons

Cited by 7 publications

References 78 publications

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

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

Therapeutic value of homeoprotein signaling pathways

The limb dorsoventral axis: Lmx1b's role in development, pathology, evolution, and regeneration

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