Sara phosphorylation state controls the dispatch of endosomes from the central spindle during asymmetric division

Abstract

During asymmetric division, fate assignation in daughter cells is mediated by the partition of determinants from the mother. In the fly sensory organ precursor cell, Notch signalling partitions into the pIIa daughter. Notch and its ligand Delta are endocytosed into Sara endosomes in the mother cell and they are first targeted to the central spindle, where they get distributed asymmetrically to finally be dispatched to pIIa. While the processes of endosomal targeting and asymmetry are starting to be understood, the machineries implicated in the final dispatch to pIIa are unknown. We show that Sara binds the PP1c phosphatase and its regulator Sds22. Sara phosphorylation on three specific sites functions as a switch for the dispatch: if not phosphorylated, endosomes are targeted to the spindle and upon phosphorylation of Sara, endosomes detach from the spindle during pIIa targeting.

Emerging mechanisms of asymmetric stem cell division

“…In parallel, the internalized pool of Delta and Notch is associated with the Smad anchor for receptor activation (Sara) endosomes, which are trafficked to pIIa cells during cytokinesis, enhancing Notch activation in pIIa cells (Coumailleau et al, 2009). This biased segregation of Sara endosomes into pIIa is mediated by biased MT orientation at the central spindle, whereby more plus ends are oriented toward the pIIa side and the kinesin-like protein at 98A carries Sara endosomes toward the pIIa cell (Derivery et al, 2015; Loubéry et al, 2017). The Sara endosomes have been shown to segregate asymmetrically in other cell types as well, such as zebrafish neural precursor cells (Kressmann et al, 2015) and Drosophila intestinal stem cells (Montagne and Gonzalez-Gaitan, 2014), suggesting the conservation of this mechanism in generating fate asymmetry.…”

Co-translational targeting of transcripts to endosomes

“…Endosomes distribute asymmetrically in polarized cells, which plays important roles in cellular polarization (eg. brush border formation in enterocytes) 40 , in asymmetric cell division 41 , and in maintaining the stemness of pluripotent cells [42][43][44] . Combining multiplexed mRNA and protein readouts with RNA sequencing of organelle fractions and quantitative proteomics [17][18][19]24,45,46 will be instrumental to study the role of subcellular transcript patterning in determining the phenotypic state of single cells and cell collectives, and their ability to display complex patterns of cellular decision making.…”

Fine-Tuning the TGFβ Signaling Pathway by SARA During Neuronal Development

“…Although several reports have described in detail the regulation of TGFβ pathway ( Wrana et al, 1994 ; Massague, 1998 ; Massague and Chen, 2000 ), our work stress the action of non-canonical regulators like SARA, a protein usually associated with endosomes and trafficking machinery. Previous studies have described that the trafficking of SARA endosomes plays a crucial role during the development of D. melanogaster and D. rerio , determining the fate of neuronal precursors during cell division ( Loubery et al, 2014 , 2017 ; Derivery et al, 2015 ; Kressmann et al, 2015 ). In addition to trafficking functions, these works suggest that SARA endosomes are also related to the regulation of cell signaling, such as the Notch/Delta pathway ( Coumailleau et al, 2009 ; Loubery et al, 2014 ; Kressmann et al, 2015 ).…”