Basal condensation of Numb and Pon complex via phase transition during Drosophila neuroblast asymmetric division

Abstract

Uneven distribution and local concentration of protein complexes on distinct membrane cortices is a fundamental property in numerous biological processes, including Drosophila neuroblast (NB) asymmetric cell divisions and cell polarity in general. In NBs, the cell fate determinant Numb forms a basal crescent together with Pon and is segregated into the basal daughter cell to initiate its differentiation. Here we discover that Numb PTB domain, using two distinct binding surfaces, recognizes repeating motifs within Pon in a previously unrecognized mode. The multivalent Numb-Pon interaction leads to high binding specificity and liquid-liquid phase separation of the complex. Perturbations of the Numb/Pon complex phase transition impair the basal localization of Numb and its subsequent suppression of Notch signaling during NB asymmetric divisions. Such phase-transition-mediated protein condensations on distinct membrane cortices may be a general mechanism for various cell polarity regulatory complexes.

Wnt/Beta-Catenin Signaling Regulation and a Role for Biomolecular Condensates

“…Looking more globally, it is an exciting time for the Wnt signaling field and for the broader arena of signaling pathway and biomolecular condensate research. Virtually every week brings new examples of cellular structures assembled by phase separation (e.g., Du and Chen, 2018;Shan et al, 2018) or defining the mechanisms by which they assemble (e.g., Harmon et al, 2017;Rai et al, 2018;Zeng et al, 2018). The new insights described above, supporting the perspective that the destruction complex and signalosome should be viewed as biomolecular condensates, open a wide variety of new directions and questions for research that can be addressed using ever more powerful tools ranging from in vitro reconstitution to in vivo genetic analysis to molecular modeling.…”

RNAs, Phase Separation, and Membrane‐Less Organelles: Are Post‐Transcriptional Modifications Modulating Organelle Dynamics?

“…Generally, BioMCs have been conceptualized as RNP‐containing hubs in which complex biochemical reactions such as splicing, processing, and maturation of specific RNAs as well as metabolic turnover of various cellular components take place. However, particular BioMCs contribute also to specific biological processes such as polarity establishment and cellular identity in early embryos (i.e., P granules and RNP segregation in C. elegans ), asymmetric cell division of stem cells in Drosophila , transcription, heterochromatin formation, DNA repair, genome integrity through nuage‐affiliated processes, or the response to biotic and abiotic stress through the formation of SGs …”

Switching states: dynamic remodelling of polarity complexes as a toolkit for cell polarization

“…Anterior-enriched MEX-5 locally suppresses phase separation through competition with P granule components for RNA binding sites, ultimately restricting P granules to the posterior [ 51 , 52 ]. LLPS has been proposed to play a role in numerous polarity pathways, including in the segregation of basal fate determinants Pon/Numb in Drosophila neuroblasts [ 53 ]. Theoretical work suggests a unique feature of LLPS in cell polarity may be its ability to lock in a polar distribution of phase separated material following a transient stimulus without additional energy input [ 54 ].…”

“…Spatial regulation of a molecule’s ability to partition into droplets allows them to be retained asymmetrically. See [ 50 , 51 , 53 , 83 ]. (d) Capture of randomly diffusing molecules by immobile anchors represents an extreme case of diffusion-based retention mechanism.…”