sox17 Mutagenesis Reveals Compounding Effects ofMaternal and Zygotic Contribution on Microglia Abundance.
Sox17 mutations can significantly impact microglia abundance in zebrafish, with maternal genotype playing a crucial role in these effects.
Where it sits
this study against the rest of the hmg (human menopausal gonadotropin) corpusSummary and findings
This study investigates the effects of sox17 mutations on microglia abundance in zebrafish, focusing on maternal and zygotic contributions. A reduction of microglia in the brain and precursors in the yolk sac was observed, with exacerbated deficits in homozygous offspring from homozygous parents. The research highlights the importance of both maternal and offspring genotypes in neurodevelopmental outcomes.
Abstract
Embryonic development is shaped by maternal and zygotic factors but how the interplay between these factors contributes to phenotypic variability and impacts specific populations of brain cells, and subsequently neurodevelopment, remains largely unknown. Here, we reveal a double hit phenomenon that impacts microglia and microglia precursors during development. Using zebrafish, we identified a mutation in sry-related HMG box gene-17 (sox17) that exhibits a maternal effect phenotype presenting as a reduction of microglia in the brain and precursors in the yolk sac. We demonstrate that microglia deficits are exacerbated in homozygous offspring from homozygous parents compared to homozygous offspring from heterozygous parents, suggesting a compounding effect of maternal and zygotic sox17 mutation on microglia abundance. We observe that sox17 is expressed in microglia and yolk sac precursors and is maternally contributed. Injections of sox17 RNA during embryogenesis are sufficient to rescue microglia and yolk sac cell abundance. To identify additional genes interacting with sox17, we perform a genetic screen using CRISPR mutagenesis and identify f11r.1, gas6, and mpp1 as microglia regulators, which we demonstrate are expressed in zebrafish microglia. Transcriptional and mutant analyses with these genes suggest sox17 positively regulates mpp1 transcription. These results demonstrate that microglia are susceptible to additive effects of maternal and zygotic sox17 mutation, and that offspring greatly differ in their susceptibility to microglia deficits depending on the mother's genotype. Our findings highlight that both the maternal and offspring genotype should be considered when examining neurodevelopmental disorders that could arise from microglia dysfunction.
Background
This paper addresses the role of maternal and zygotic factors in embryonic development, particularly their impact on microglia populations. Prior research has established the importance of these factors, but the specific mechanisms and interactions remain largely unexplored. Understanding these interactions is crucial for elucidating the etiology of neurodevelopmental disorders linked to microglia dysfunction.
Methods
The study utilized zebrafish as a model organism to investigate the effects of sox17 mutations. Specific genetic mutations were introduced using CRISPR mutagenesis, and the impact on microglia and yolk sac cell abundance was assessed. The primary outcomes included the abundance of microglia and precursors, with secondary outcomes involving the identification of additional interacting genes.
Results
The study found that sox17 mutations lead to a reduction of microglia in the brain and yolk sac precursors. Homozygous offspring from homozygous parents exhibited exacerbated microglia deficits compared to those from heterozygous parents. Injections of sox17 RNA were shown to rescue the abundance of these cells.
Interpretation
These findings suggest that both maternal and zygotic contributions are critical in determining microglia abundance during development. While the results are statistically significant, the clinical relevance in human neurodevelopmental disorders remains uncertain due to the use of zebrafish models. The study's limitations include the potential lack of direct applicability to human conditions and the absence of detailed quantitative measures.
Key findings
- Reduction of microglia in the brain and precursors in the yolk sac due to sox17 mutation.
- Microglia deficits are exacerbated in homozygous offspring from homozygous parents compared to those from heterozygous parents.
- Injections of sox17 RNA during embryogenesis are sufficient to rescue microglia and yolk sac cell abundance.
Limitations
- Based on zebrafish models, which may not fully translate to human data.
- Specific quantitative effects of mutations on microglia abundance were not detailed.
- Small sample size and potential genetic variability in zebrafish.
- Focus on a single gene (sox17) without broader context on other influencing factors.