Mathonnet, G. | Search bioRxiv

bioRxiv2026

Asymmetric distribution of actin-related proteins in the early C. elegans embryo.

Embryos experience challenges when transforming a passive oocyte into a polarized embryo. In Caenorhabditis elegans, polarisation is initiated at the one-cell stage and followed by a series of asymmetric or symmetric cell divisions. Patterns emerge via the regulated segregation of molecules at each cell division, including polarity proteins, cell fate determinants, transcription factors, mRNAs, and actin. The actomyosin cytoskeleton plays a crucial role in these early differentiation events, but how actin itself is segregated asymmetrically during the first divisions of the zygote remains poorly understood. This study presents a thorough quantification of the spatiotemporal distribution of actin, the actin nucleators CYK-1 and Arp2/3 Complex, the capping protein CAP-1, and the E-cadherin HMR-1, from the zygote up to the 4-cell stage. To determine the potential for actin assembly of each early embryonic cell, we developed a novel assay combining in vivo microscopy-based quantitative analysis of the cytoskeleton, with in vitro actin polymerisation assays from single cell extracts named SCOPE-Single Cell cytOPlasm Extraction. SCOPE relies on UV laser ablation to empty blastomere cells into a polymerisation competent environment while following subsequent actin polymerisation. We find asymmetric segregations of most cytoskeleton proteins in favour of larger cells in a manner that is dependent on PAR polarity cues. AB and EMS cells being notably actively enriched compared to their sister cells, P cells being maintained in a state of low actin filaments. Interestingly, we discover an enrichment in ABp compared to ABa as division occurs, demonstrating that symmetric cell divisions are not exempt of actin enrichment. Additionally, this result illustrates that asymmetric distribution of actin-related proteins can precede known cell differentiation events. Taken together, these cytoskeleton heterogeneities are adding a layer to the complexity of cell fate acquisition mechanisms in the early embryo. Significance StatementO_LIThe embryonic cytoskeleton can be actively inherited rather than passively distributed during early development. C_LIO_LIActin assembly capacity can differ between blastomeres before fate diversification. C_LIO_LIDifferential inheritance of actin regulatory machinery represents a potential mechanism linking cell polarity to developmental cell fate decisions. C_LI

developmental biology↗

bioRxiv2020

Estimating the effect-size of gene dosage on cognitive ability across the coding genome

Genomic Copy Number Variants (CNVs) are routinely identified and reported back to patients with neuropsychiatric disorders, but their quantitative effects on essential traits such as cognitive ability are poorly documented. We have recently shown that the effect-size of deletions on cognitive ability can be statistically predicted using measures of intolerance to haploinsufficiency. However, the effect-sizes of duplications remain unknown. It is also unknown if the effect of multigenic CNVs are driven by a few genes intolerant to haploinsufficiency or distributed across tolerant genes as well. Here, we identified all CNVs >50 kilobases in 24,092 individuals from unselected and autism cohorts with assessments of general intelligence. Statistical models used measures of intolerance to haploinsufficiency of genes included in CNVs to predict their effect-size on intelligence. Intolerant genes decrease general intelligence by 0.8 and 2.6 points of IQ when duplicated or deleted, respectively. Effect-sizes showed no heterogeneity across cohorts. Validation analyses demonstrated that models could predict CNV effect-sizes with 78% accuracy. Data on the inheritance of 27,766 CNVs showed that deletions and duplications with the same effect-size on intelligence occur de novo at the same frequency. We estimated that around 10,000 intolerant and tolerant genes negatively affect intelligence when deleted, and less than 2% have large effect-sizes. Genes encompassed in CNVs were not enriched in any GOterms but gene regulation and brain expression were GOterms overrepresented in the intolerant subgroup. Such pervasive effects on cognition may be related to emergent properties of the genome not restricted to a limited number of biological pathways.

genetics↗