DOI: 10.5061/dryad.qbzkh18vj
title: S1PR1 regulates lymphatic valve development and prevents ileitis-independent tertiary lymphoid organ formation

description: Lymphatic vessels function throughout the body to drain interstitial
 fluids. Efficient lymph flow is ensured by lymphatic valves (LVs).
 However, the mechanisms that regulate LV development are incompletely
 understood. Here, we show that the deletion of the GPCR sphingosine
 1-phosphate receptor-1 (S1PR1) from lymphatic endothelial cells (LECs)
 results in fewer LVs. Interestingly, LVs that remained in the
 terminal-ileum draining lymphatic vessels were specifically dysfunctional,
 and tertiary lymphoid organs (TLOs) formed in this location. TLOs in the
 terminal ileum are associated with ileitis in humans and mice. However,
 mice lacking S1PR1 did not develop obvious characteristics of ileitis.
 Sphingosine kinases 1 and 2 (SPHK1/2) are required for the synthesis of
 S1P, the ligand of S1PR1. Mice that lack Sphk1/2 in LECs recapitulate the
 LV and TLO phenotypes of mice that lack S1PR1. Mechanistically, S1PR1
 regulates shear stress signaling and the expression of the
 valve-regulatory molecules FOXC2 and connexin-37. Importantly, Foxc2+/-
 mice, a model for lymphedema-distichiasis syndrome, also develop TLOs in
 the terminal ileum. Thus, we have discovered S1PR1 as a previously unknown
 regulator of LV and TLO development. We also suggest that TLOs are a sign
 of subclinical inflammation that can form due to lymphatic disorders in
 the absence of ileitis.
description: # S1PR1 Regulates Lymphatic Valve Development And Tertiary Lymphoid Organ
 Formation Dataset DOI: [10.5061/dryad.qbzkh18vj](10.5061/dryad.qbzkh18vj)
 ## Description of the data and file structure S1pr1f/f and
 Tg(Prox1-CreERT2); S1pr1f/f mice were administered tamoxifen from
 postnatal days 1-7. Fecal pellets were collected from the mice for
 metagenomic sequencing when they were 10 months old. The file names and
 the genotypes of mice are provided below. FS38995605- Tg(Prox1-CreERT2);
 S1pr1f/f FS38995667- Tg(Prox1-CreERT2); S1pr1f/f FS38995819- S1pr1f/f
 FS38995785- S1pr1f/f FS38995546- S1pr1f/f ### Files and variables ####
 File: FS38995605.fastq **Description:** Metagenomic analysis of fecal
 pellets from 10-month-old Tg(Prox1-CreERT2); S1pr1f/f (tamoxifen from
 P1-7) mouse-1. #### File: FS38995667.fastq **Description:** Metagenomic
 analysis of fecal pellets from 10-month-old Tg(Prox1-CreERT2); S1pr1f/f
 (tamoxifen from P1-7) mouse-2. #### File: FS38995785.fastq
 **Description:** Metagenomic analysis of fecal pellets from 10-month-old
 S1pr1f/f (tamoxifen from P1-7) mouse-1. #### File: FS38995819.fastq
 **Description:** Metagenomic analysis of fecal pellets from 10-month-old
 S1pr1f/f (tamoxifen from P1-7) mouse-2. #### File: FS38995546.fastq
 **Description:** Metagenomic analysis of fecal pellets from 10-month-old
 S1pr1f/f (tamoxifen from P1-7) mouse-3. ## Code/software The data was
 analyzed using One Codex cloud-based software that was provided to us by
 the company that sequenced our samples (Transnetyx, Memphis, TN, USA).
 More information about the analysis is available from the One Codex
 website
 ([https://docs.onecodex.com/en/articles/3761205-one-codex-database](https://docs.onecodex.com/en/articles/3761205-one-codex-database)).