Lauren Shechtman

UC San Francisco

“RasGRP1 signaling regulates tuft cell generation in mouse small intestine”

Tuft cells are rare chemosensory cells, which reside in the epithelial lining of the small intestine (SI) and initiate type 2 immune responses upon worm infection. Specifically, tuft cells signal to innate lymphocytes to produce cytokines that trigger an immune response and enhance tuft cell production. However, many questions remain regarding what epithelial-intrinsic signals drive tuft cell generation and maturation during homeostasis and infection. The Ras exchange factor, RasGRP1 is expressed in the SI crypt; our studies with RasGRP1 deficient mice (Rasgrp1-/-) reveal altered crypt proliferation, suggesting RasGRP1 may also govern epithelial fate decisions. Using a spectral flow panel capable of detecting SI epithelial cell types, we discovered that Rasgrp1-/- intestines contain fewer tuft cells, leading to delayed worm clearance. Conversely, induced expression of Rasgrp1 driven by Villin-Cre, promotes tuft cell production, and enhances helminth clearing. Our single cell RNAseq analyses point to reduced tuft cell lineage potential in Rasgrp1-/- mice. Informed by these data, we are currently manipulating signaling cues in organoids to mechanistically evaluate the epithelial circuit contributing to tuft cell generation.

ABSTRACT

Tuft cells are rare chemosensory cells in the gut that initiate type II immune responses upon infection. To maintain proper function, these cells only live ~3-5 days, and are continuously replenished by intestinal stem cells (ISCs); however, it’s still unclear what epithelial signals govern intestinal stem and progenitor cells towards tuft cell fate. Data from the Roose lab, suggests the Ras exchange factor, Rasgrp1, may contribute to this trajectory; I therefore use genetic mouse models, single cell RNA sequencing, and organoid technology to dissect whether Rasgrp1 drives tuft cell differentiation in the small intestine.
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