TALE and Hox Transcription Factors Modulate Adult Behaviors in Zebrafish

Zebrafish frk Gene Knockout Shows Social Impairments Relevant to Autism and Delays Brain Development by Increasing Cell Proliferation

An autism model of frk‐knockout with an assessable behavior phenotype in zebrafish is established and key insights into cell proliferation and the influence of the cyp24a1/tp53 pathway‐regulated cell proliferation on frk‐knockout‐induced autism‐like behaviors are provided.

Loss of neurofibromin alters adult metabolism via effects during a developmental critical period

Cross-species variant-to-function analyses implicate MEIS1 in conferring sleep abnormalities and impaired cerebellar development.

Genome-wide association studies (GWAS) have identified numerous loci for insomnia, yet functional validation of effector genes remains limited because most risk variants lie in noncoding regions, and the true causal gene is not known. Here, we use prior human cell-based variant-to-gene mapping to nominate six insomnia effector genes and test them in zebrafish, a tractable diurnal vertebrate model well-suited for sleep phenotyping. Our CRISPR-based behavioral screening identifies the MEIS1 ortholog, meis1b, as a regulator of sleep maintenance, with crispants displaying impaired nighttime-specific sleep maintenance and increased sleep latency. Comparative chromatin analyses reveal conserved regulatory architecture spanning the human insomnia-associated locus and selectively implicate meis1b, whereas the duplicated ohnolog meis1a was dispensable. Developmental profiling further shows that meis1b is expressed in cerebellar granule progenitors, paralleling human MEIS1 expression, and that its disruption impairs cerebellar development. Together, these findings establish zebrafish as an efficient vertebrate platform for functional interrogation of GWAS candidates and support an evolutionarily conserved cerebellar role for MEIS1 in sleep maintenance.

Multiple molecular pathways to longevity with opposing gene expression programs defining distinct aging strategies in Caenorhabditis elegans

While aging is the greatest risk factor for the development of neurodegenerative disease, the role of aging in these diseases is poorly understood. Our previous work has shown that targeting aging pathways can be neuroprotective in animal models of neurodegenerative disease. Based on these findings, we believe that by gaining insight into the aging process that knowledge can be applied to identify novel therapeutic targets for neurodegenerative disease. To advance our understanding of aging, we used a genomics approach to identify genes regulated by multiple lifespan-extending pathways. We performed RNA sequencing on nine long-lived Caenorhabditis elegans mutants representing seven longevity pathways: insulin/IGF-1 signaling, dietary restriction, germline deficiency, impaired chemosensation, reduced translation, elevated mitochondrial ROS, and mild mitochondrial impairment. We found that most pairs of long-lived mutants exhibited a significant overlap in differentially expressed genes. Comparing gene expression across the entire panel of long-lived mutants revealed three distinct longevity groups that could be clearly distinguished by gene expression. Interestingly, two of these groups showed modulation of specific genetic pathways in opposite directions, suggesting that there are multiple alternative strategies to achieving long life. Filtering for genes similarly modulated in at least six mutants identified 196 upregulated and 62 downregulated aging genes. Upregulated genes were enriched in immunity, defense, and metabolism, while many downregulated genes impacted translation and gene expression. To assess the ability of these genes to enhance longevity individually, we knocked down the commonly upregulated genes in long-lived mutants and evaluated the resulting effect on lifespan. Using this approach, we identified several genes that affect lifespan individually. Upregulation of at least some of these genes was sufficient to enhance stress resistance and extend lifespan in wild-type worms. Overall, the shared longevity genes identified in this work offer potential targets to promote healthy aging and decrease age-onset disease.

MAP3K1 Integrates Genetic and Environmental Signals in Eyelid Morphogenesis

Developmental disorders often arise from complex interactions between genetic variation and environmental factors, yet the molecular mechanisms underlying gene-gene (G × G) and gene-environment (G × E) interactions remain poorly understood. Mouse embryonic eyelid closure provides a genetically tractable in vivo model for investigating these mechanisms. Eyelid closure requires coordinated epithelial migration and cytoskeletal remodeling orchestrated by interconnected signaling pathways. Among these pathways, MAP3K1 functions as a critical signaling hub that integrates inputs from S1PR-RHOA-ROCK and other upstream regulators to activate JNK and promote eyelid closure. Genetic studies show that multiple components within the GPCR-RHOA-ROCK-MAP3K1-JNK network cooperate to maintain developmental robustness. Reducing the activity of pathway components dose-dependently impairs eyelid closure and produces the characteristic eye-open-at-birth (EOB) phenotype. Environmental factors also converge on this network. Although exposure to dioxin does not impair eyelid closure in wild-type embryos, it induces EOB in embryos harboring otherwise phenotypically silent mutations in the MAP3K1 network, such as Map3k1+/−, Jnk1−/− and S1pr2−/−. These findings identify the MAP3K1 pathway as a point of convergence of genetic and environmental signals and establish embryonic eyelid closure as a powerful model for elucidating molecular mechanisms underlying developmental robustness, susceptibility and resilience.

Molecules and Cells