Mother cell inheritance and regulation of SYS-1/β-catenin during Wnt-driven asymmetric cell divisions in C. elegans.
Creators: name: Valdes Michel, Maria F.
Publisher: name: University of Iowa
Year: 2025
Subjects: APR-1
asymmetric cell division
beta-catenin
C. elegans
SYS-1
Wnt
Cellular biology

description: Asymmetric cell division (ACD) allows daughter cells of a polarized mother to acquire different developmental fates. In C. elegans , the Wnt/β-catenin Asymmetry (WβA) pathway oversees many embryonic and larval ACDs; here, a Wnt gradient induces an asymmetric distribution of Wnt signaling components within the dividing mother cell. This process allows the daughter cells to differentially regulate Wnt target genes giving rise to a Wnt-dependent and Wnt-independent lineage. One terminal nuclear effector of the WβA pathway is the transcriptional activator SYS-1/β-catenin. SYS-1 is sequentially negatively regulated during ACD; first by centrosomal regulation and subsequent proteasomal degradation and second by asymmetric activity of the β-catenin "destruction complex" in one daughter cell, which decreases SYS-1 levels in the absence of WβA signaling.
description: Previously, our lab showed that SYS-1 centrosomal localization is dependent on the centrosomal scaffold protein RSA-2 and dynein trafficking. Additionally, once trafficked to the centrosomal locale, previous data suggest SYS-1 is degraded by a centrosomally localized proteosome. Also known as SYS-1 centrosomal processing, the trafficking and centrosomal degradation of SYS-1 regulates and prevents over-inheritance of SYS-1. Here, we tested if the over-inheritance of mother cell SYS-1 due to impaired centrosomal processing will result in a symmetric Wnt-signaled cell division. Using ACD of distal tip cell lineage (DTC), the Wnt signaled daughter cell of a larval ACD, we found that impairment of mother cell centrosomal processing resulted in extra DTCs. Additionally, we used a Phs::SYS-1, which acts as a sensitized background that displays more Wnt-signaled cells and was enhanced by loss of centrosomal trafficking, coupling or degradation in the DTC lineage and the seam cells, another larval Wnt signaled ACD. This suggests that the role of SYS-1 centrosomal processing is to limit SYS-1 inheritance during ACD and is required for robust cell fate determination mechanisms.
description: However, the extent to which mother cell SYS-1 normally influences cell fate decisions of the daughters is unknown. Here, we quantify inherited SYS-1 in the differentiating daughter cells and the role of SYS-1 inheritance in Wnt-directed ACD. Photobleaching experiments demonstrate the GFP::SYS-1 present in daughter cell nuclei is comprised of inherited and de novo translated SYS-1 pools. We used a photoconvertible DENDRA2::SYS-1, to directly observe the dynamics of inherited SYS-1 during the ACD of the EMS cell. We focused on the first Wnt driven asymmetric cell division of the C. elegans embryo, the EMS cell division, which specifies the Wnt-signal E cell and the unsignaled MS cell. Photoconversion during mitosis reveals that SYS-1 clearance at the centrosome preferentially degrades older SYS-1, and this accumulation is regulated via dynein trafficking. Photoconversion of the EMS cell during Wnt-driven ACD shows daughter cell inheritance of mother cell SYS-1. Consistent with our model, loss of centrosomal SYS-1 increased inherited SYS-1, however, surprisingly, loss of centrosomal SYS-1 also resulted in increased levels of de novo SYS-1 in both EMS daughter cells. Lastly, we show that daughter cell negative regulation of SYS-1 via the destruction complex member APR-1/APC is key to limit both the de novo and the inherited SYS-1 pools in both the E and the MS cells, even though APR-1 is not required to limit SYS-1 levels in the EMS mother cell. We conclude that regulation of both inherited and newly translated SYS-1 via centrosomal processing in the mother cell and daughter cell regulation via Wnt signaling are critical to maintain sister SYS-1 asymmetry during ACD.