Biology subjects

Ben Driss, L.

Publications and source records attributed to Ben Driss, L..

4 recordsLinked to original sources

bioRxiv2026

Recombinant GDF11 Improves Neurological Recovery in Models of Hemorrhagic Stroke and Traumatic Brain Injury

BackgroundIntracerebral hemorrhage (ICH) and traumatic brain injury (TBI) are leading causes of long-term neurological disability and mortality worldwide, with no approved therapies that promote functional recovery. Growth differentiation factor 11 (GDF11), a circulating TGF{beta}-family protein, has shown regenerative and neurorestorative potential in models of ischemic stroke. MethodsWe evaluated recombinant GDF11 (rGDF11) in mouse models of ICH and TBI. ICH was induced by intrastriatal collagenase injection, and neurological recovery was assessed using Neuroseverity Score (NSS), Rotarod (RR), and CatWalk (CW) analyses up to 28 days post-injury. Histological assessments of vascularization, neuronal density, and microglial/macrophage density were performed 28 days after ICH. For TBI, a closed-head injury model using a pneumatic impactor was employed, and NSS and RR assessments were conducted through 28 days post-injury. ResultsrGDF11 treatment significantly improved neurobehavioral performance following ICH, including NSS, RR, and CW parameters (forelimb base of support and average speed). Histological analyses revealed enhanced vascular area and neuronal density, with reduced microglial/macrophage density in rGDF11-treated mice. Following TBI, rGDF11 accelerated functional recovery, improving RR latency by day 6 and NSS by day 28 post-injury. ConclusionrGDF11 promotes structural and functional recovery after both hemorrhagic and traumatic brain injury in mice. These findings, together with prior evidence in ischemic stroke, support rGDF11 as a promising neurorestorative biologic with broad therapeutic potential for diverse forms of brain injury. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=178 SRC="FIGDIR/small/730114v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@8c624forg.highwire.dtl.DTLVardef@8a6107org.highwire.dtl.DTLVardef@e83ce6org.highwire.dtl.DTLVardef@f65f14_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2026

EYA1/EYA2 and EYA3/EYA4 act as stage-specific SIX cofactors in embryonic and adult regenerative skeletal myogenesis

Eya3 and Eya4 are two Eya genes expressed in adult myogenic stem cells, where they may act as SIX cofactors. We analyzed muscle regeneration in single and compound Eya3 and satellite cell-specific Eya4 mutant mice. A kinetic analysis of muscle regeneration after Notexin injury of the Tibialis Anterior revealed no major phenotype at 4, 14, and 30 days after injury in terms of PAX7+ cell number and myofiber cross-sectional area in Eya3 mutants, while all parameters were decreased in Eya4 mutants and further worsened in Eya3/Eya4 double mutants, in which we also observed a modification of the myofiber phenotype at 30 days after injury. Satellite cells were cultured ex vivo and Eya4 deletion was induced by Ad-Cre-mediated recombination. While single Eya3 mutant cells showed normal proliferation and differentiation, double mutant cells exhibited normal proliferation but failed to fuse. Analysis of their transcriptome revealed that the expression of Myomixer, Follistatin, and Noggin was severely downregulated specifically in double mutant cells, explaining their fusion deficiency. To gain a better understanding of the involvement of Eya genes during embryonic development and the genesis of PAX7+ myogenic stem cells, we analyzed Eya1 / ;Eya2 / , Eya3 / , Eya4 / , and Eya3 / ;Eya4 / E18.5 mutant fetuses at the limb and craniofacial levels. In Eya1 / ;Eya2 / fetuses, we confirmed the absence of distal limb muscles and observed reduced craniofacial muscles. In Eya3 / ;Eya4 / fetuses, craniofacial myogenesis appeared preserved and PAX7+ myogenic stem cells were present. BackgroundThe Eyes absent (Eya) genes encode transcriptional co-activators and phosphatases that function within the PAX-SIX-EYA-DACH (PSED) regulatory network. In skeletal muscle, EYA proteins cooperate with SIX homeoproteins to control myogenic gene expression during both embryonic development and adult regeneration. While Eya1 and Eya2 are predominantly expressed in embryonic myogenic progenitors and Eya3 and Eya4 are the dominant paralogs in adult satellite cells (SC), the specific and redundant contributions of individual family members to myogenesis remain poorly characterized. MethodsWe analyzed compound Eya mutant mice during adult Tibialis anterior muscle regeneration and during embryogenesis. We complemented this analysis by performing ex vivo myogenic stem cell cultures from compound Eya mutants and examining their fusion capacity. ResultsAnalysis of muscle regeneration following Notexin injury revealed that Eya2 and Eya3 single mutants display no major regenerative deficit. In contrast, satellite cell-specific deletion of Eya4 (Eya4sc/sc) caused a transient impairment of early regeneration, with reduced numbers of smaller regenerating MYH3+ (embryonic myosin heavy chain) myofibers and a transient decrease in SC number at 4 days post-injury (dpi). Compound Eya3-/-;Eya4sc/scdouble mutants showed a more severe and persistent phenotype, with decreased myofiber cross-sectional area, reduced myonuclear accretion, accumulation of PAX7+ cells associated with regenerated myofibers, and altered fiber-type composition at 14 and 30 dpi. Ex vivo analysis of double mutant SCs revealed a specific and complete blockade of myogenic fusion without defects in proliferation or MYOD expression. Transcriptomic analysis identified severe downregulation of Myomixer, Noggin, and Follistatin in differentiating Eya3-/-;Eya4-/- SCs. Open-access SIX1 and SIX4 ChIP-seq publicly available data confirmed direct binding at the Myomixer, Noggin, and Follistatin loci, supporting a direct SIX-EYA transcriptional mechanism. In parallel, embryonic analysis demonstrated that Eya1-/-;Eya2-/-E18.5 fetuses lack distal limb musculature and display severe craniofacial muscle hypoplasia, while in Eya3-/-;Eya4-/-fetuses limb and craniofacial musculature developed with no detectable defects. ConclusionsThese results reveal distinct temporal requirements for EYA proteins in skeletal muscle: EYA1 and EYA2 are essential SIX cofactors for embryonic myogenic fate acquisition in hypaxial and craniofacial progenitors, while EYA3 and EYA4 act redundantly in adult satellite cells to enable myogenic fusion by maintaining BMP antagonist expression and Myomixer activation downstream of the SIX-EYA transcriptional complex.

developmental biology↗

bioRxiv2026

Microbiome depletion rejuvenates the aging brain

Aging is associated with cognitive decline and increased vulnerability to neurodegeneration driven by an array of molecular and cellular changes like impaired vascular integrity, demyelination, reduced neurogenesis, and chronic inflammation. Recent studies implicate the gut microbiome as a modulator of brain aging, but the underlying mechanisms remain elusive. Here, we show that depleting the gut microbiome by administering antibiotics to aged mice induces widespread molecular and structural rejuvenation in the brain. Our transcriptomic analyses by single-nucleus RNA sequencing revealed pronounced transcriptional shifts across multiple brain cell types. We confirmed that antibiotic treatment improves vascular density, promotes myelination, enhances neurogenesis, and reduces microglial reactivity. Functionally, microbiome-depleted mice showed improved hippocampal memory performance. Analyses of brain and plasma cytokine levels showed a decrease in several pro-inflammatory factors post-treatment and identified candidate factors, including the chemokine eotaxin-1. Inhibiting eotaxin-1 alone can reverse several aspects of brain aging. Our findings demonstrate that age-associated microbial inflammation contributes to brain aging and that its attenuation can restore youthful features at the molecular, cellular, and functional levels. Targeting the gut microbiome or its circulating mediators may therefore represent a non-invasive approach to promote brain health and cognitive resilience in aging.

neuroscience↗

bioRxiv2021

LRRFIP2 modulates the response to hypoxia during embryonic cardiogenesis

Oxygen is crucial for appropriate embryonic and fetal development, including cardiogenesis. The heart is the first organ formed in the embryo and is required to provide oxygen and nutrients to all cells in the body. Embryonic cardiogenesis is a complex process finely regulated and prone to congenital malformations. It takes place in a hypoxic environment that activates the HIF-1 signaling pathway which mediates cellular and systemic adaptations to low oxygen levels. Since inhibition or overactivation of the HIF-1 signaling pathway in the myocardium lead to severe cardiac malformations and embryonic lethality, it is important that the cellular response to hypoxia be precisely regulated. While many gene regulatory networks involved in embryonic cardiogenesis have been characterized in detail, the modulation of the response of cardiomyocytes (CM) to hypoxia has remained less studied. We identified LRRFIP2 as a new negative cofactor of HIF-1. Indeed, we have shown that the absence of Lrrfip2 expression in a mouse KI model led to an enhance of many HIF-1 target genes including Igfbp3, Bnip3 and Ndufa4l2 in embryonic CM during development. As results, the absence of Lrrfip2 led to the inhibition of the PI3K/Akt survival pathway, growth defects, mitochondrial dysfunction and to a precocious maturation of the embryonic CMs. Altogether, these defects led to the formation of a smaller heart unable to provide sufficient oxygen to the embryo and finally to a severe hypoxia and a precocious lethality. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=199 HEIGHT=200 SRC="FIGDIR/small/472540v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@1cb5836org.highwire.dtl.DTLVardef@10c7b97org.highwire.dtl.DTLVardef@86263aorg.highwire.dtl.DTLVardef@137da51_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LILRRFIP2 regulates negatively the HIF-1 activity C_LIO_LILrrfip2 deletion leads to an embryonic lethality between E11.5 and E13.5 C_LIO_LILRRFIP2 controls ROS production and CM maturation C_LI

developmental biology↗