Biology subjects

Marty, V.

Publications and source records attributed to Marty, V..

4 recordsLinked to original sources

bioRxiv2026

The DGKK mRNA is a primary target of the Prader-Willi syndrome-associated snoRNA SNORD116

Box C/D small nucleolar RNAs (SNORDs) classically guide site-specific modification of ribosomal RNAs through antisense elements located upstream of their D[prime] and D boxes, termed ASE1 and ASE2. Yet many orphan SNORDs have no established primary targets, including the paternally expressed multicopy SNORD116 family implicated in Prader-Willi syndrome. Our previous comparative analysis identified the DGKK/Dgkk interaction as the most evolutionarily persistent candidate involving the highly conserved SNORD116 ASE1 sequence and showed that SNORD116 depletion increases DGKK RNA abundance in human cells. Here, we re-evaluated this interaction alongside a focused set of recently published candidates and asked whether evolutionary persistence was accompanied by independent evidence of regulation. DGKK/Dgkk showed reproducible increases following transient SNORD116 loss across human iPSC-derived neural cells and in brain tissues from Snord116-knockout mice. Its predicted SNORD116 interaction site combined a marked local depletion of human sequence variation with an overlapping cis-regulatory interval identified in mouse. SNORD116 deficiency was also associated with increased endogenous DGK[kappa]; protein across several mouse brain regions, including the hypothalamus. More broadly, comparison across the candidate set showed that evolutionary persistence, duplex stability and expression response did not systematically align, indicating that sequence-based properties alone do not allow reliable prediction of responses to SNORD116 loss. Together, these data support DGKK/Dgkk as the best-supported primary regulatory target of SNORD116 to date and establish it as a model for dissecting the regulatory mechanism of this orphan snoRNA family.

molecular biology↗

bioRxiv2026

Evolutionary and biological insights into the paternally expressed Snord116-Ipw-Snord115 gene array at the imprinted Prader-Willi syndrome domain

Placental mammal-specific box C/D small nucleolar RNA (SNORD) genes within the imprinted human 15q11q13 domain have garnered increasing attention because their poorly understood roles in the brain and their potential involvement in Prader-Willi syndrome (PWS). Using two novel knockout (KO) mouse models, we demonstrate that combined deletion of Snord116 and Snord115 genes, but not the intervening Ipw ncRNA gene, leads to partially penetrant perinatal lethality (40-50%). Snord116/115-deficient neonates display postnatal growth impairment, hypoglycemia and endocrine dysregulation, including failure of the postnatal leptin surge. Despite showing no overt alterations in feeding behavior, adult Snord116/115-KO mice recapitulate most phenotypes previously reported in Snord116-KO models. RNA-seq analyses of the hypothalamus, prefrontal cortex and cerebellum reveal limited global changes. However, we observed upregulation of two of the most compelling putative RNA targets of Snord116 and Snord115 (Dgkk and Htr2c, respectively) in the postnatal hypothalamus. Nevertheless, no evidence was found to support efficient Snord115-guided ribose methylation of Htr2c mRNA. Finally, comparative analyses across 64 representative placental mammal species reveal that many PWS-associated SNORD genes, including SNORD115, display greater evolutionary changes than previously appreciated, raising questions about the functional relevance and evolutionary selective pressures that have shaped the diversification of certain family members across species. Overall, our study provides an unbiased re-assessment of the evolutionary, molecular and physiological significance of the paternally expressed Snord116-Ipw-Snord115 genomic interval and highlights the early postnatal period as a critical, yet largely underexplored, developmental window during which recently evolved SNORDs likely function as dispensable fine-tuners of gene expression.

genetics↗

bioRxiv2026

Loss of SNORD115 mitigates SNORD116-driven sleep abnormalities in mouse models of Prader-Willi syndrome

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder caused by the loss of paternally expressed genes within the imprinted 15q11-q13 locus, which includes clusters of box C/D small nucleolar RNAs (SNORDs), notably the SNORD115 and SNORD116 gene families. Although paternally inherited SNORD116 deletions have been associated with sleep disturbances in patients and mouse models, the respective and combined contributions of SNORD115 and SNORD116 to sleep regulation remain unclear. Here, we combined polysomnographic recordings with quantitative analysis of hypothalamic neuronal populations to assess sleep-wake architecture, sleep homeostasis, and underlying circuit alterations in mice carrying paternal deletions of SNORD115, SNORD116, or both clusters. SNORD116 deletion was associated with a selective increase in REM sleep, particularly during the light phase and during recovery following sleep deprivation, without affecting slow-wave sleep or REM-associated theta activity. In contrast, SNORD115 deletion did not alter sleep. Unexpectedly, combined deletion of SNORD115 and SNORD116 did not reproduce the REM sleep phenotype observed in SNORD116-deficient mice, indicating that SNORD115 loss attenuates SNORD116-dependent REM sleep alterations. At the cellular level, melanin-concentrating hormone (MCH) neuron density was reduced in both SNORD116-KO and double SNORD116/115-KO mice, whereas hypocretin (Hcrt) neurons were preserved across genotypes. Notably, REM sleep alterations did not parallel MCH loss, as increased REM sleep was absent in double-KO animals despite comparable reduction in MCH neuron density. Transcriptomic analyses at ZT0 further revealed only limited changes in hypothalamic gene expression across models. Together, these findings reveal an unanticipated interaction between SNORD115 and SNORD116 in the regulation of REM sleep and uncover a dissociation between genetic alterations, neuronal circuit organization, and sleep phenotype. More broadly, they caution against inferring physiological functions or disease-relevant mechanisms from single SNORD deletions within complex imprinted loci, and indicate that current mouse models may not faithfully capture sleep alterations associated with PWS.

neuroscience↗

bioRxiv2020

Sex-dependent effects of chronic intermittent voluntary alcohol consumption on attentional, not motivational, measures during probabilistic learning and reversal

BackgroundForced alcohol (ethanol, EtOH) exposure has been shown to cause significant impairments on reversal learning, a widely-used assay of cognitive flexibility, specifically on fully-predictive, deterministic versions of this task. However, previous studies have not adequately considered voluntary EtOH consumption and sex effects on probabilistic reversal learning. The present study aimed to fill this gap in the literature. MethodsMale and female Long-Evans rats underwent either 10 weeks of voluntary intermittent 20% EtOH access or water only (H2O) access. Rats were then pretrained to initiate trials and learn stimulus-reward associations via touchscreen response, and subsequently required to select between two visual stimuli, rewarded with probability 0.70 or 0.30. In the final phase, reinforcement contingencies were reversed. ResultsWe found significant sex differences on several EtOH-drinking variables, with females reaching a higher maximum EtOH consumption, exhibiting more high-drinking days, and escalating their EtOH at a quicker rate compared to males. During early abstinence, EtOH drinkers made more initiation omissions and were slower to initiate trials than H2O drinking controls, particularly during pretraining. EtOH drinking females were most affected. A similar pattern in trial initiations was also observed in discrimination, but not in reversal learning. EtOH drinking rats were unaffected in their reward collection and stimulus response times, indicating intact motivation and motor responding. Although there were sex differences in discrimination and reversal phases, performance improved over time. We also observed sex-independent drinking group differences in win-stay and lose-shift strategies specific to the reversal phase. ConclusionsFemales exhibit increased vulnerability to EtOH effects in early learning: there were sex-dependent EtOH effects on attentional measures during pretraining and discrimination phases. We also found sexindependent EtOH effects on exploration strategies during reversal. Future studies should aim to uncover the neural mechanisms for changes in attention and exploration in both acute and prolonged EtOH withdrawal.

pharmacology and toxicology↗