A new role for Notch in the control of polarity and asymmetric cell division of developing T cells

Abstract

A fundamental question in biology is how single cells can reliably produce progeny of different cell types. Notch signalling frequently facilitates fate determination. Asymmetric cell division (ACD) often controls segregation of Notch signalling by imposing unequal inheritance of regulators of Notch. Here, we assessed the functional relationship between Notch and ACD in mouse T cell development. To attain immunological specificity, developing T cells must pass through a pivotal stage termed β-selection,

Developing T cells form an immunological synapse for passage through the β-selection checkpoint

“…1, C–E ). As previously found ( Charnley et al, 2019 ; Pham et al, 2015 ), the cytokine receptor CD25 was not polarized ( Fig. 1 C ).…”

“…Our previous observation that the MTOC was recruited to the interface with the stromal cell ( Charnley et al, 2019 ; Pham et al, 2015 ), reminiscent of an immunological synapse in mature cells ( Alcover et al, 2016 ; Dustin and Baldari, 2017 ), led us to assess whether developing T cells might also form an immunological synapse. Flow cytometry confirmed that pre-TCR components, including the pTα chain, TCRβ chain, LCK, LAT, and PKCθ, were expressed in DN3 cells.…”

“…Given that the pre-TCR has only limited affinity for MHC–peptide complexes, we speculated that the recruitment of pre-TCR components to the interface with the stromal cell might depend upon other receptors. The fate determinant Notch1 and the chemokine receptor CXCR4 play essential roles in driving T cell development at the β-selection checkpoint ( Maillard et al, 2006 ; Trampont et al, 2010 ; Charnley et al, 2019 ), cooperate with pre-TCR signaling ( Garbe et al, 2006 ; Zhao et al, 2019 ), and are localized at the DN3-OPL-DL1 stromal cell interface ( Pham et al, 2015 ; Fig. S2 ).…”

“…The affinity of the interaction is lower than that of the αβ TCR ( Mallis et al, 2015 ), suggesting the possibility that binding of the pre-TCR might require facilitation by other molecules. We and others have previously found that the interaction between stromal cells and developing T cells at the β-selection checkpoint involves recruitment of the microtubule organizing center (MTOC), a hallmark of initiation of the immunological synapse ( Charnley et al, 2019 ; Martín-Cófreces et al, 2008 ; Pham et al, 2015 ). This finding, combined with the interaction between pre-TCR and stromal cell MHC, opened the possibility that an immunological synapse might facilitate TCR signaling during β-selection.…”

From kidney injury to kidney cancer

“…25 Notch has an important role in control of polarity and orientation of the mitotic spindle in several cell types. 25,[137][138][139] Indeed, aberrant Notch activation disrupted cell polarity signaling, leading to a notable number of abnormal mitoses in renal progenitors, through the deregulation of pathways involved in cell cycle checkpoints and/or mitotic spindle control. 25 Hippo pathway.…”