Biology subjects

Reich, S.

Publications and source records attributed to Reich, S..

6 recordsLinked to original sources

bioRxiv2025

Exacerbation of a Subset of Behavioral Phenotypes by Early Treatment with AAV FOXG1 Gene Replacement Therapy in a Mouse Model of FOXG1 Syndrome

FOXG1 syndrome is a severe neurodevelopmental disorder characterized by microcephaly, profound intellectual disability with communication deficits including lack of speech, impaired social interaction, increased anxiety, hyperkinetic/dyskinetic movements, seizures and abnormal sleep patterns. Mutations in a single allele of the FOXG1 gene cause disease, likely due to loss-of-function. However, current therapies do not target this root cause of FOXG1 syndrome and have little to modest therapeutic benefit on only a small subset of symptoms. Recently, we reported the beneficial effects of adeno-associated virus (AAV) human FOXG1 gene replacement therapy administered by intracerebroventricular (ICV) injection at postnatal day 6 (P6) on several behavioral deficits that are relevant to key features of human FOXG1 syndrome, in male FOXG1 mice that were engineered with a highly prevalent, patient-specific Q84P mutation. Here, we report the behavioral effects of AAV human FOXG1 gene replacement therapy administered by ICV injection in female as well as male mice and at an earlier age - postnatal day 2 (P2). Although the earlier studies had suggested that AAV FOXG1 gene replacement therapy is a promising approach for the treatment of a subset of functional deficits in human FOXG1 syndrome with no toxicity observations, our current study shows that certain motor behaviors can be negatively impacted or exacerbated by P2 treatment with AAV FOXG1 gene replacement therapy, in female but not male FOXG1 mice. Given these results, the risk-benefit balance of AAV FOXG1 gene replacement therapy in patients with FOXG1 syndrome should be carefully considered, especially in female patients.

neuroscience↗

bioRxiv2025

Behavioral Efficacy of AAV FOXG1 Gene Replacement Therapy in a Mouse Model of FOXG1 Syndrome

FOXG1 syndrome is a severe neurodevelopmental disorder characterized by microcephaly, profound intellectual disability with communication deficits including lack of speech, impaired social interaction, increased anxiety, hyperkinetic/dyskinetic movements, seizures and abnormal sleep patterns. Mutations in a single allele of the FOXG1 gene cause disease, likely due to loss-of-function. However, current therapies do not target this root cause of FOXG1 syndrome and have little to modest therapeutic benefit on only a small subset of symptoms. To date, the therapeutic potential of restoring FOXG1 levels in the brain with adeno-associated virus (AAV) FOXG1 gene replacement therapy has only been reported in a Foxg1fl/+;NexCre mouse model that lacks one Foxg1 allele but does not express mutant FOXG1, and with only neuroanatomical endpoints evaluated. Here, in a FOXG1 mouse model that contains a highly prevalent, patient-specific Q84P mutation, we describe the beneficial effects of AAV human FOXG1 gene replacement therapy administered by intracerebroventricular (ICV) injection at postnatal day 6 (P6) on several behavioral deficits that are relevant to key features of human FOXG1 syndrome. Our studies demonstrate that AAV FOXG1 gene replacement therapy is a promising approach for the treatment of a subset of functional deficits in human FOXG1 syndrome.

neuroscience↗

bioRxiv2024

Developmental transcriptomics in Pristionchus reveals the logic of a plasticity gene regulatory network

Developmental plasticity enables the production of alternative phenotypes in response to different environmental conditions. While significant advances in understanding the ecological and evolutionary implications of plasticity have been made, understanding its genetic basis has lagged. However, a decade of genetic screens in the model nematode Pristionchus pacificus has culminated in 30 genes which affect mouth-form plasticity. We also recently reported the critical window of environmental sensitivity, and therefore have clear expectations for when differential gene expression should matter. Here, we collated previous data into a gene-regulatory network (GRN), and performed developmental transcriptomics across different environmental conditions, genetic backgrounds, and mouth-form mutants to assess the regulatory logic of plasticity. We found that only two genes in the GRN (eud-1 and seud-1/sult-1) are sensitive to the environment during the critical window. Interestingly, the time points of their sensitivity differ, suggesting that they act as sequential checkpoints. We also observed temporal constraint upon the transcriptional effects of mutating the GRN and revealed unexpected feedback between mouth-form genes. Surprisingly, expression of seud-1/sult-1, but not eud-1, correlated with mouth form biases across different strains and species. Finally, a comprehensive analysis of all samples identified metabolism as a shared pathway for regulating mouth-form plasticity. These data are presented in a Shiny app to facilitate gene-expression comparisons across development in up to 14 different conditions. Collectively, our results suggest that mouth-form plasticity evolved a constrained, two-tiered logic to integrate environmental information leading up to the final developmental decision.

genetics↗

bioRxiv2023

Halophilic nematodes live in America's Dead Sea

Extremophiles can reveal the origins of life on Earth and the possibility of life elsewhere. Most identified extremophiles are single-cell microbes, leaving gaps in our knowledge concerning the origins and habitable limits of multicellular organisms. Here, we report the recovery of roundworms (Phylum Nematoda) from the Great Salt Lake (GSL), UT, a hypersaline lake referred to as "Americas Dead Sea". Nematodes were found primarily in microbialites, benthic organosedimentary structures once abundant on early Earth. 16S sequencing of individual nematodes revealed a diverse bacterial community distinct from its surrounding habitat. Phylogenetic divergence compared to Owens Lake, another terminal lake in the Great Basin, suggests that GSL nematodes represent multiple previously undescribed species. These findings update our understanding of halophile ecosystems and the habitable limit of animals. One-Sentence SummaryWe report the discovery of novel halophilic nematodes in microbialites of the Great Salt Lake, UT.

ecology↗

bioRxiv2020

A Mathematical Model of Exploration and Exploitation in Natural Scene Viewing

Understanding the decision process underlying gaze control is an important question in cognitive neuroscience with applications in diverse fields ranging from psychology to computer vision. The decision for choosing an upcoming saccade target can be framed as a dilemma: Should the observer further exploit the information near the current gaze position or continue with exploration of other patches within the given scene? While several models attempt to describe the dynamics of saccade target selection, none of them explicitly addresses the underlying Exploration-Exploitation dilemma. Here we propose and investigate a mathematical model motivated by the Exploration-Exploitation dilemma in scene viewing. The model is derived from a minimal set of assumptions that generates realistic eye movement behavior. We implemented a Bayesian approach for model parameter inference based on the models likelihood function. In order to simplify the inference, we applied data augmentation methods that allowed the use of conjugate priors and the construction of an efficient Gibbs sampler. This approach turned out to be numerically efficient and permitted fitting interindividual differences in saccade statistics. Thus, the main contribution of our modeling approach is two-fold; first, we propose a new model for saccade generation in scene viewing. Second, we demonstrate the use of novel methods from Bayesian inference in the field of scan path modeling. Author summaryThe Exploration-Exploitation dilemma is general concept that has been investigated in human information processing. We investigate whether the Exploration-Exploitation trade-off is a viable approach to model sequences of fixations generated by a human observer in a free viewing task with natural scenes. Variants of the basic model are used to predict to the experimental data based on Bayesian inference. Results indicate a high predictive power for both aggregated data and individual differences across observers. The combination of a novel model with state-of-the-art Bayesian methods lends support to the Exploration-Exploitation framework in the field of eye-movement research.

neuroscience↗

bioRxiv2018

Altered chromatin localization of hybrid lethality proteins in Drosophila

Understanding hybrid incompatibilities is a fundamental pursuit in evolutionary genetics. In crosses between Drosophila melanogaster females and Drosophila simulans males, the interaction of at least three genes is necessary for hybrid male lethality: Hmr mel, Lhr sim, and gfzf sim. All three hybrid incompatibility genes are chromatin associated factors. While HMR and LHR physically bind each other and function together in a single complex, the connection between either of these proteins and gfzf remains mysterious. Here, we investigate the allele specific chromatin binding patterns of gfzf. First, our cytological analyses show that there is little difference in protein localization of GFZF between the two species except at telomeric sequences. In particular, GFZF binds the telomeric retrotransposon repeat arrays, and the differential binding of GFZF at telomeres reflects the rapid changes in sequence composition at telomeres between D. melanogaster and D. simulans. Second, we investigate the patterns of GFZF and HMR co-localization and find that the two proteins do not normally co-localize in D. melanogaster. However, in inter-species hybrids, HMR shows extensive mis-localization to GFZF sites, and this altered localization requires the presence of gfzf sim. Third, we find by ChIP-Seq that over-expression of HMR and LHR within species is sufficient to cause HMR to mis-localize to GFZF binding sites, indicating that HMR has a natural low affinity for GFZF sites. Together, these studies provide the first insights into the different properties of gfzf between D. melanogaster and D. simulans as well as a molecular interaction between gfzf and Hmr in the form of altered protein localization.

molecular biology↗