Labus, J. | Search bioRxiv

bioRxiv2026

Ectopic expression of the germline transcription factor LSL-1 contributes to developmental delay following failed maternal epigenetic reprogramming

Proper transmission of cell identity between generations requires maternal epigenetic reprogramming mechanisms that prevent inappropriate inheritance of lineage-specific transcriptional programs. In Caenorhabditis elegans, loss of the H3K4me1/2 demethylase SPR-5 and the H3K9 methyltransferase MET-2 results in ectopic expression of germline genes in somatic tissues and severe developmental delay. Previous studies demonstrated that the chromatin regulator MES-4 contributes to these defects, but whether germline-specific transcription factors also participate in the ectopic transcriptional program remained unclear. Here, we investigated the role of the germline transcription factor LSL-1 in animals lacking SPR-5 and MET-2. We found that genes normally regulated by LSL-1 in the germline are significantly overrepresented among genes ectopically expressed in the soma of spr-5; met-2 progeny. Consistent with this observation, an endogenously tagged LSL-1 protein became ectopically expressed throughout somatic tissues when maternal SPR-5 and MET-2 activity was disrupted. Furthermore, depletion of LSL-1 partially suppressed the developmental delay observed in spr-5; met-2 mutants. Transcriptomic analyses revealed extensive overlap between MES-4- and LSL-1-dependent transcriptional programs, with most LSL-1-dependent genes also requiring MES-4. Notably, ectopic expression of lsl-1 itself depended on MES-4, suggesting that LSL-1 functions downstream of MES-4. Genes dependent on LSL-1 were strongly enriched for germline-associated expression programs and included previously identified direct LSL-1 targets. Together, our findings support a model in which MES-4 promotes ectopic expression of LSL-1, which in turn contributes to a shared germline-associated transcriptional program and developmental delay following failed maternal epigenetic reprogramming. These results demonstrate how lineage-restricted transcription factors cooperate with inherited chromatin states to reinforce aberrant transcriptional programs and disrupt cell fate boundaries.

developmental biology↗

bioRxiv2026

A conserved serotonin receptor pathway is a druggable modifier of Tau pathology, neural circuit formation and neurodegeneration

Tauopathies are devastating neurodegenerative disorders characterized by Tau hyperphosphorylation, neurofibrillary tangle (NFT) formation, neuronal dysfunction, and cognitive decline. Here, we establish a new Drosophila tauopathy model expressing eGFP-tagged human TauWT or the disease-associated TauP301L variant in the nervous system. TauP301L expression recapitulates key pathological and behavioral hallmarks of tauopathy, including elevated Tau hyperphosphorylation, accumulation of NFT-like, pTau-positive assemblies in vivo, reduced lifespan, hyperactivity, sleep loss, progressive locomotor decline, and age-dependent brain degeneration. Strikingly, TauP301L also disrupts the architecture of the mushroom body, a learning- and memory-related circuit in Drosophila, revealing an early disruption of neural circuit formation that is distinct from adult neurodegenerative phenotypes. We further show that suppression of serotonin 5-HT7R-CDK5 signaling pathway, either by genetic knockdown or pharmacological inhibition with inverse agonist, rescues Tau-induced behavioral and anatomical phenotypes. These findings identify 5-HT7R signaling as a conserved and druggable modifier of Tau toxicity and establish this model as a powerful in vivo platform for mechanistic studies and therapeutic discovery in tauopathies.

neuroscience↗