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  • Cell-autonomous retinoic acid receptor signaling has stage-specific effects on mouse enteric nervous system.

Cell-autonomous retinoic acid receptor signaling has stage-specific effects on mouse enteric nervous system.

JCI insight (2021-04-14)
Tao Gao, Elizabeth C Wright-Jin, Rajarshi Sengupta, Jessica B Anderson, Robert O Heuckeroth
ABSTRACT

Retinoic acid (RA) signaling is essential for enteric nervous system (ENS) development, since vitamin A deficiency or mutations in RA signaling profoundly reduce bowel colonization by ENS precursors. These RA effects could occur because of RA activity within the ENS lineage or via RA activity in other cell types. To define cell-autonomous roles for retinoid signaling within the ENS lineage at distinct developmental time points, we activated a potent floxed dominant-negative RA receptor α (RarαDN) in the ENS using diverse CRE recombinase-expressing mouse lines. This strategy enabled us to block RA signaling at premigratory, migratory, and postmigratory stages for ENS precursors. We found that cell-autonomous loss of RA receptor (RAR) signaling dramatically affected ENS development. CRE activation of RarαDN expression at premigratory or migratory stages caused severe intestinal aganglionosis, but at later stages, RarαDN induced a broad range of phenotypes including hypoganglionosis, submucosal plexus loss, and abnormal neural differentiation. RNA sequencing highlighted distinct RA-regulated gene sets at different developmental stages. These studies show complicated context-dependent RA-mediated regulation of ENS development.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Collagenase from Clostridium histolyticum, for general use, Type I, ≥125 CDU/mg solid
Sigma-Aldrich
SYBR® Green JumpStart Taq ReadyMix, for quantitative PCR, MgCI2 in buffer
Sigma-Aldrich
Benzyl ether, 98%